Pyrimidone compounds and pharmaceutical compositions containing the same

ABSTRACT

The invention provides novel pyrimidone compounds exhibiting excellent antagonism against adenosine receptors (A 1 , A 2A , and A 2B  receptors), particularly, compounds represented by the general formula (1), salts thereof, or solvates of both: (1) wherein R 1  and R 2  are each independently hydrogen, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-8  cycloalkyl, C 3-8  cycloalkenyl, a 5- to 14-membered nonaromatic heterocyclic group, a C 6-14  aromatic hydrocarbon group, a 5- to 14-membered aromatic heterocyclic group, C 1-6  acyl, or C 1-6  alkylsulfonyl; R 3  is hydrogen, C 1-6  alkyl, C 2-6  alkenyl, or C 2-6  alkynyl; R 4  is a C 6-14  aromatic hydrocarbon group; a 5- to 14-membered aromatic heterocyclic group, or a 5- to 14-membered nonaromatic heterocyclic group having at least one unsaturated bond; and R 5  is a C 6-14  aromatic hydrocarbon group or a 5- to 14-membered aromatic heterocyclic group (with the proviso that every group except hydrogen may be substituted).

FIELD OF THE INVENTION

The present invention relates to a novel pyrimidone compound, aproduction process thereof, and a pharmaceutical preparation containingit and use thereof.

PRIOR ART

Adenosine is an important regulatory factor involved in manyintracellular metabolisms in the living body, such as regulation ofenergy levels and cAMP (cyclic adenosine monophosphate) levels, openingand closing potassium channels, and inflow of calcium ions into cells,and its interaction with G protein-coupled adenosine receptors on thesurface of a cell is essential for exhibiting these physiologicalactivities.

Adenosine receptors were classified under two subtypes, A₁ receptor andA₂ receptor based on the involvement in adenylate cyclase (J.Neurochem., Vol. 33, p 999–1003, (1979)), and thereafter, the A₂receptor has been classified under two subtypes, A_(2A) and A_(2B),based on the affinity for A₂ receptor agonists, NECA and CGS-21680 (Mol.Pharmacol., Vol. 29, p. 331–346, (1986); J. Neurochem., Vol. 55, p.1763–1771, (1990)). Four receptor subtypes, A₁, A₂ (A_(2A) and A_(2B))and A₃, have been identified until now. The A₁ receptor is a proteincoupled receptor with a G_(i/o) family of proteins. It serves to inhibitthe adenylate cyclase as a result of binding with a ligand to therebydecrease the cAMP level and serves to activate phospholipase C (PLC) tothereby promote the production of inositol-1,4,5-triphosphate (IP₃) andto release the intracellular calcium ions. The A₃ receptor is a receptorserving to decrease the cAMP level and to activate PLC to therebypromote the IP₃ production and the release of calcium ions, as the A₁receptor. In contrast, the A_(2A) and A_(2B) receptors are receptorsserving to activate the adenylate cyclase and promote the production ofcAMP. There is a report that the A_(2B) receptor couples with PLC via aG_(q)/G₁₁ protein or promotes the production of IP₃ and the flow ofcalcium ions into cells (Clin. Invest. Vol. 96, p. 1979–1986 (1995)).

These subtypes are different from one another in their distribution intissues; that is, the A₁ receptor occurs relatively abundantly, forexample, in the heart, aorta and bladder, the A_(2A) receptor isdistributed relatively abundantly, for example, in the eyeballs andskeletal muscles, the A₃ receptor, for example, in the spleen, uterus,and prostate, and the A_(2B) receptor, for example, in the proximalcolon, and subsequently in the eyeballs, lung, uterus and bladder (Br.J. Pharmacol., Vol. 118, p. 1461–1468 (1996)). It is believed that theseadenosine receptor subtypes can exhibit specific functions,respectively, due to the difference in distribution in the tissues aswell as the difference in adenosine level among the locations and thedifference in affinity for the ligand among the subtypes.

Adenosine is involved in a variety of physiological functions, such asplatelet aggregation, heart rate, smooth muscle tonus, inflammation,release of neurotransmitters, neurotransmission, hormone release,cell-differentiation, cell growth, cell death, and DNA biosynthesis.Accordingly, the relation between adenosine and diseases, such ascentral nervous system diseases, cardiovascular diseases, inflammatorydiseases, respiratory diseases, and immune diseases, has been suggested,and the efficacy of agonists/antagonists of the adenosine receptors onthese diseases has been expected. Antagonists against the adenosinereceptors, particularly those against the adenosine A₂ receptors havebeen discussed as effective as an agent for treating or preventingdiabetes mellitus, diabetic complications, diabetic retinopathy, obesityor asthma and have been expected useful as, for example, a hypoglycemicagent, an agent for improving glucose intolerance, an insulinsensitizer, a hypotensive agent, a diuretic agent, an agent for treatingosteoporosis, an agent for treating Parkinson's disease, an agent fortreating Alzheimer's disease, an agent for treating an inflammatorybowel disease, or an agent for treating Crohn's disease.

Certain important reports have been made on the relation between theadenosine A₂ receptor and the intestinal tract. For example, certainreports have been made that the A₂ receptor mediates a colonlongitudinal muscle relaxation action (Naunyn-Schmiedeberg's Arch.Pharmacol., 359, 140–146 (1999)), and that the A₁ receptor, and theA_(2B) receptor occurring in the longitudinal muscle mediate arelaxation action of adenosine against the contraction of distal colonlongitudinal muscle of a guinea pig (Br. J. Pharmacol., 129, 871–876(2000)). Such A_(2B) receptor antagonists do not induce diarrhea, havean excellent defecation-promoting action and are expected as an agentfor treating and/or preventing various constipation. They are alsoexpected as being useful for treating and/or preventing irritable bowelsyndrome, constipation accompanying irritable bowel syndrome, organicconstipation or constipation accompanying enteroparalytic ileus and forevacuating intestinal tracts at the time of examination of digestivetracts or before and after an operation.

For example, the following compounds (1)–(3) have been reported ashaving an antagonism against the A_(2B) receptor.

(1) Compounds represented by the formulae:

(2) A purine derivative represented by the formula:

(wherein R¹ represents (1) the formula:

(wherein X represents a hydrogen atom, a hydroxyl group, a lower alkylgroup which may be substituted, a lower alkoxy group which may besubstituted, etc.; and R⁵ and R⁶ are the same as or different from eachother and each represents a hydrogen atom, a lower alkyl group which maybe substituted, a saturated or unsaturated cycloalkyl group having threeto eight carbon atoms which may be substituted, etc.) or (2) a 5 or6-membered aromatic ring which may have one or more substituents and ahetero atom; W represents the formula: —CH₂CH₂—, —CH═CH— or —C≡C—; R²represents an amino group which may be substituted with a lower alkylgroup which may be substituted, etc.; R³ represents a cycloalkyl grouphaving three to eight carbon atoms which may be substituted, an arylgroup which may be substituted, etc.; and R⁴ represents a lower alkylgroup which may be substituted, etc.), a pharmacologically acceptablesalt thereof or a hydrate of them (JP-A 11-263789).(3) A purine compound represented by the formula:

(wherein R¹ represents a hydrogen atom, a hydroxyl group, a halogenatom, an alkyl group having one to eight carbon atoms which may besubstituted, etc.; R² represents an amino group which may be substitutedwith an alkyl group having one to eight carbon atoms, etc.; R³represents an alkynyl group having three to eight carbon atoms which maybe substituted with a halogen atom, a hydroxyl group or an alkyl grouphaving one to four carbon atoms, etc.; Ar represents an aryl group whichmay be substituted, a heteroaryl group which may be substituted, etc.;and Q and W are the same as or different from each other and eachrepresents N or CH), a pharmacologically acceptable salt thereof or ahydrate of them (JP-A 11-188484).(4) A_(2B) receptor antagonists described in Drug Development Research,48: 95–103 (1999) and J. Med. Chem., 43: 1165–1172 (2000).

In contrast, pyrimidone compounds have been only reported as compoundsin, for example, WO 98/24780. However, the relation between thesecompounds and the adenosine receptors has been neither reported norsuggested and has not yet been known.

As is described above, compounds having an adenosine receptorantagonism, among them, compounds having an adenosine A₂ receptorantagonism, and particularly compounds having an A_(2B) receptorantagonism are expected to exhibit an excellent action as a medicament,and strong demands have been made to provide such compounds. However,compounds which have an excellent antagonism against the adenosinereceptors and effectively act as a medicament have not yet been found.Accordingly, an object of the present invention is to search for andfind compounds which serve to inhibit the adenosine receptors (inparticular A₂ receptor, A_(2B) receptor) and are useful as an agent fortreating or preventing a disease to which the adenosine receptorsrelate.

DISCLOSURE OF THE INVENTION

After intensive investigations under these circumstances, the presentinventors have succeeded, for the first time, to synthesize a compoundrepresented by the formula:

(in the formula, R¹ and R² are the same as or different from each otherand each represents a hydrogen atom, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic cyclic hydrocarbon group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R³ represents a hydrogen atom, analkyl group having one to six carbon atoms which may be substituted, analkenyl group having two to six carbon atoms which may be substituted oran alkynyl group having two to six carbon atoms which may besubstituted; R⁴ represents an aromatic cyclic hydrocarbon group havingsix to fourteen carbon atoms which may be substituted, a 5 to14-membered aromatic heterocyclic group which may be substituted or a 5to 14-membered non-aromatic heterocyclic group having at least oneunsaturated bond which may be substituted; and R⁵ represents an aromaticcyclic hydrocarbon group having six to fourteen carbon atoms which maybe substituted or a 5 to 14-membered aromatic heterocyclic group whichmay be substituted), a salt thereof or a solvate of them. They haveunexpectedly found that the compound and a salt thereof have anexcellent antagonism against the adenosine A₂ receptors, particularlyagainst the A_(2B) receptor. After further intensive investigations,they have found that the compound, a salt thereof or a solvate of themhas an efficacy on diseases to which the adenosine receptors,particularly the adenosine A₂ receptors, further particularly theadenosine A_(2B) receptor relates, and that it is efficacious forpreventing and/or treating various constipation (e.g., irritable bowelsyndrome, constipation accompanying irritable bowel syndrome, organicconstipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction, orconstipation accompanying ileus) and is also useful as an agent fortreating, preventing or improving, for example, diabetes mellitus,diabetic complications, diabetic retinopathy, obesity or asthma, and asa hypoglycemic agent, an agent for improving glucose intolerance, aninsulin sensitizer, a hypotensive agent, a diuretic agent, an agent fortreating osteoporosis, an agent for treating Parkinson's disease, anagent for treating Alzheimer's disease, an agent for treating aninflammatory bowel disease or an agent for treating Crohn's disease. Thepresent invention has been accomplished based on these findings.

Specifically, the present invention relates to, for example, (1) acompound represented by the formula:

(in the formula, R¹ and R² are the same as or different from each otherand each represents a hydrogen atom, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic cyclic hydrocarbon group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, an acyl group having one to six carbon atomswhich may be substituted or an alkylsulfonyl group having one to sixcarbon atoms which may be substituted; R³ represents a hydrogen atom, analkyl group having one to six carbon atoms which may be substituted, analkenyl group having two to six carbon atoms which may be substituted oran alkynyl group having two to six carbon atoms which may besubstituted; R⁴ represents an aromatic cyclic hydrocarbon group havingsix to fourteen carbon atoms which may be substituted, a 5 to14-membered aromatic heterocyclic group which may be substituted or a 5to 14-membered non-aromatic heterocyclic group having at least oneunsaturated bond which may be substituted; and R⁵ represents an aromaticcyclic hydrocarbon group having six to fourteen carbon atoms which maybe substituted or a 5 to 14-membered aromatic heterocyclic group whichmay be substituted), a salt thereof or a solvate of them; (2) thecompound according to the above (1), a salt thereof or a solvate ofthem, wherein R⁴ is 4-pyridyl group, 4-pyrimidinyl group, 4-quinazolinylgroup, 4-quinolyl group, 6-isoquinolyl group, each of which may besubstituted, or a 5 to 14-membered non-aromatic heterocyclic grouphaving at least one of unsaturated bond which may be substituted; (3)the compound according to the above (1) or (2), a salt thereof or asolvate of them, wherein R⁴ is represented by the formula:

(wherein R⁶ represents a group selected from the following SubstituentGroup a; and the ring A may be substituted with one to four groupsselected from the following Substituent Group a: <Substituent Group a>the group consisting of a hydrogen atom, a halogen atom, a hydroxylgroup, a nitro group, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an alkoxy group having oneto six carbon atoms which may be substituted, an alkenyloxy group havingtwo to six carbon atoms which may be substituted, an alkynyloxy grouphaving two to six carbon atoms which may be substituted, an alkylthiogroup having one to six carbon atoms which may be substituted, analkenylthio group having two to six carbon atoms which may besubstituted, an alkynylthio group having two to six carbon atoms whichmay be substituted, an aliphatic acyl group having two to seven carbonatoms, a carbamoyl group which may be substituted, an arylacyl group, aheteroarylacyl group, an amino group which may be substituted, analkylsulfonyl group having one to six carbon atoms which may besubstituted, an alkenylsulfonyl group having two to six carbon atomswhich may be substituted, an alkynylsulfonyl group having two to sixcarbon atoms which may be substituted, an alkylsulfinyl group having oneto six carbon atoms which may be substituted, an alkenylsulfinyl grouphaving two to six carbon atoms which may be substituted, analkynylsulfinyl group having two to six carbon atoms which may besubstituted, a formyl group, a cycloalkyl group having three to eightcarbon atoms which may be substituted, a cycloalkenyl group having threeto eight carbon atoms which may be substituted, a 5 to 14-memberednon-aromatic heterocyclic group which may be substituted, an aromaticcyclic hydrocarbon group having six to fourteen carbon atoms which maybe substituted and a 5 to 14-membered aromatic heterocyclic group whichmay be substituted); (4) the compound according to the above (3), a saltthereof or a solvate of them, wherein R⁴ is represented by the formula:

or the formula:

(in the formulae (III) and (IV), R⁶ represents a group selected from theabove-mentioned Substituent Group a; and the ring A represents anitrogen-containing 6-membered ring which may be substituted with one tofour groups selected from the above mentioned Substituent Group a); (5)the compound according to the above (1) or (2), a salt thereof or asolvate of them, wherein R⁴ is 4-pyridyl group which may be substituted;(6) the compound according to any one of the above (1) to (5), a saltthereof or a solvate of them, wherein R¹ and/or R² is a hydrogen atom,an alkyl group having one to six carbon atoms which may be substituted,or an acyl group having one to six carbon atoms which may besubstituted; (7) the compound according to any one of the above (1) to(6), a salt thereof or a solvate of them, wherein R⁵ is phenyl group,pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group, thienyl group, thiazolyl group, furyl group, naphthylgroup, quinolinyl group, isoquinolinyl group, phthalazinyl group,naphthyridinyl group, indolyl group or isoindolyl group, each of whichmay be substituted; (8) a pharmaceutical composition comprising thecompound according to any one of the above (1) to (7), a salt thereof ora solvate of them; (9) the composition according to the above (8), whichis an agent for treating or preventing a disease to which an adenosinereceptor relates; (10) the composition according to the above (8), whichis an agent for treating or preventing a disease to which an adenosineA₂ receptor relates; (11) the composition according to the above (8),which is an agent for treating or preventing a disease to which anadenosine A_(2B) receptor relates; (12) the composition according to theabove (8), which is an adenosine receptor antagonist; (13) thecomposition according to the above (8), which is an adenosine A₂receptor antagonist; (14) the composition according to the above (8),which is adenosine A_(2B) receptor antagonist; (15) the compositionaccording to the above (8), which is a defecation-promoting agent; (16)the composition according to the above (8), which is an agent fortreating, preventing or improving constipation; (17) the compositionaccording to the above (16), wherein the constipation is functionalconstipation; (18) the composition according to the above (8), which isan agent for treating, preventing or improving irritable bowel syndrome,constipation accompanying irritable bowel syndrome, organicconstipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction orconstipation accompanying ileus; (19) the composition according to theabove (8), which is used for evacuating intestinal tracts at the time ofexamination of digestive tracts or before and after an operation; (20)use of the compound according to any one of the above (1) to (7), a saltthereof or a solvate of them for producing a defecation-promoting agent;(21) the composition according to the above (8), which is an agent fortreating or preventing diabetes mellitus, diabetic complications,diabetic retinopathy, obesity or asthma; (22) the composition accordingto the above (8), which is a hypoglycemic agent, an agent for improvingglucose intolerance or an insulin sensitizer; and (23) the compositionaccording to the above (8), which is a hypotensive agent, a diureticagent, an agent for treating osteoporosis, an agent for treatingParkinson's disease, an agent for treating Alzheimer's disease, an agentfor treating an inflammatory bowel disease or an agent for treatingCrohn's disease.

Hereinafter, the meanings of symbols, terms, etc. used in the presentdescription will be described, and the present invention will beillustrated in detail.

In the present description, the “antagonist” refers to an agent whichhas affinity for and inactivates an adenosine receptor, preferably anadenosine A₂ receptor, and more preferably an A_(2B) receptor.

The “disease to which an adenosine receptor relates” used in the presentdescription refers to a disease to which an adenosine A₁ receptor,A_(2A) receptor, A_(2B) receptor or A₃ receptor relates, and includesvarious constipation (e.g., functional constipation, irritable bowelsyndrome, constipation accompanying irritable bowel syndrome, organicconstipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction andconstipation accompanying ileus), diabetes mellitus, diabeticcomplications, diabetic retinopathy, obesity, asthma, as well asdiseases against which a hypoglycemic agent, agent for improving glucoseintolerance, insulin sensitizer, antihypertensive drug, diuretic agent,agent for treating osteoporosis, agent for treating Parkinson's disease,agent for treating Alzheimer's disease, agent for treating aninflammatory bowel disease or agent for treating Crohn's disease isefficacious.

The present invention provides a method for treating or preventing adisease to which an adenosine receptor relates, and a method forpromoting defecation, which comprises administering a pharmacologicallyeffective dose of the compound represented by the formula (I), a saltthereof or a solvate of them to a patient.

The present invention further provides use of the compound representedby the formula (I), a salt thereof or a solvate of them for producing anagent for treating or preventing a disease to which an adenosinereceptor relates, or a defecation-promoting agent.

The compound represented by the formula (I), a salt thereof or a solvateof them is also useful as a defecation-promoting agent and is used forevacuating intestinal tracts at the time of examination of digestivetracts or before and after an operation.

The term “and/or” used in the present description means and includesboth the cases of “and” and “or”.

In the present description, there is the case where the structuralformula of a compound represents a definite isomer for the sake ofconvenience. However, the present invention includes all isomers such asgeometrical isomers, optical isomers based on asymmetric carbon,stereoisomers and tautomers, and mixtures of these isomers and is notlimited by the description of the formula illustrated for the sake ofconvenience. The compound can be any of isomers or a mixture thereof.Accordingly, although it is possible that an asymmetric carbon atom ispresent in a molecule and that optically active substance and racemicsubstance may therefore be present, the present invention is not limitedthereto but covers any of them. Further, crystal polymorphism may bepresent but, again, there is no limitation but any of single crystalform or a mixture will do. The compound (I) or its salt according to thepresent invention may be a non-solvate or a solvate, and either of themare included in the scope of claims for patent in the present invention.A metabolite which is generated by decomposing the compound (I)according to the present invention in vivo, and a prodrug of thecompound (I) or its salt according to the present invention are alsoincluded in the scope of claims for patent in the present invention.

The “halogen atom” used in the present description represents an atomsuch as fluorine atom, chlorine atom, bromine atom or iodine atom, andfluorine atom, chlorine atom and bromine atom are preferred.

The “C₁₋₆ alkyl group” used in the present description represents analkyl group having one to six carbon atoms, including linear or branchedalkyl groups such as methyl group, ethyl group, n-propyl group,iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group,t-butyl group, n-pentyl group, 1,1-dimethylpropyl group,1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group,2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group,1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group,1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group,1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutylgroup, 2-methylpentyl group or 3-methylpentyl group.

The “C₂₋₆ alkenyl group” used in the present description represents analkenyl group having two to six carbon atoms, and suitable examples ofthe group are vinyl group, allyl group, 1-propenyl group, 2-propenylgroup, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenylgroup, 2-methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenylgroup, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenylgroup, 1,3-hexadienyl group and 1,6-hexadienyl group.

The “C₂₋₆ alkynyl group” used in the present description represents analkynyl group having two to six carbon atoms, and suitable examples ofthe group are ethynyl group, 1-propynyl group, 2-propynyl group,1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynylgroup, 1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynylgroup, 1-hexynyl group, 1,3hexadiynyl group, and 1,6-hexadiynyl group.

The “C₁₋₆ alkoxy group” used in the present description represents analkoxy group having one to six carbon atoms, such as methoxy group,ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group,n-butoxy group, iso-butoxy group, sec-butoxy group, t-butoxy group,n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxygroup, iso-hexoxy group, 1,1-dimethylpropyloxy group,1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxygroup, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group,1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group,1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxygroup, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxygroup, 3-methylpentoxy group or hexyloxy group.

The “C₂₋₆ alkenyloxy group” used in the present description representsan alkenyloxy group having two to six carbon atoms, and suitableexamples of the group are vinyloxy group, allyloxy group, 1-propenyloxygroup, 2-propenyloxy group, isopropenyloxy group, 2-methyl-1-propenyloxygroup, 3-methyl-1-propenyloxy group, 2-methyl-2-propenyloxy group,3-methyl-2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group,3-butenyloxy group, 1-pentenyloxy group, 1-hexenyloxy group,1,3-hexadienyloxy group, and 1,6-hexadienyloxy group.

The “C₂₋₆ alkynyloxy group” used in the present description representsan alkynyloxy group having two to six carbon atoms, and suitableexamples thereof are ethynyloxy group, 1-propynyloxy group,2-propynyloxy group, 1-butynyloxy group, 2-butynyloxy group,3-butynyloxy group, 3-methyl-1-propynyloxy group,1-ethynyl-2-propynyloxy group, 2-methyl-3-propynyloxy group,1-pentynyloxy group, 1-hexynyloxy group, 1,3-hexadiynyloxy group, and1,6-hexadiynyloxy group.

The “alkylthio group having one to six carbon atoms” used in the presentdescription refers to an alkylthio group having one to six carbon atoms,such as methylthio group, ethylthio group, n-propylthio group,iso-propylthio group, sec-propylthio group, n-butylthio group,iso-butylthio group, sec-butylthio group, t-butylthio group,n-pentylthio group, iso-pentylthio group, sec-pentylthio group,n-hexylthio group, iso-hexylthio group, 1,1-dimethylpropylthio group,1,2-dimethylpropylthio group, 2,2-dimethylpropylthio group,2-ethylpropylthio group, 1-methyl-2-ethylpropylthio group,1-ethyl-2-methylpropylthio group, 1,1,2-trimethylpropylthio group,1,1-dimethylbutylthio group, 1,2-dimethylbutylthio group,2,2-dimethylbutylthio group, 2,3-dimethylbutylthio group,1,3-dimethylbutylthio group, 2-ethylbutylthio group, 2-methylpentylthiogroup or 3-methylpentylthio group.

The “alkenylthio group having two to six carbon atoms” used in thepresent description refers to an alkenylthio group having two to sixcarbon atoms, and suitable examples thereof are vinylthio group,allylthio group, 1-propenylthio group, 2-propenylthio group,isopropenylthio group, 2-methyl-1-propenylthio group,3-methyl-1-propenylthio group, 2-methyl-2-propenylthio group,3-methyl-2-propenylthio group, 1-butenylthio group, 2-butenylthio group,3-butenylthio group, 1-pentenylthio group, 1-hexenylthio group,1,3-hexadienylthio group, and 1,6-hexadienylthio group.

The “alkynylthio group having two to six carbon atoms” used in thepresent description represents an alkynylthio group having two to sixcarbon atoms, and suitable examples thereof are ethynylthio group,1-propynylthio group, 2-propynylthio group, 1-butynylthio group,2-butynylthio group, 3-butynylthio group, 3-methyl-1-propynylthio group,1-ethynyl-2-propynylthio group, 2-methyl-3-propynylthio group,1-pentynylthio group, 1-hexynylthio group, 1,3-hexadiynylthio group, and1,6-hexadiynylthio group.

The “cycloalkyl group having three to eight carbon atoms” used in thepresent description represents a cycloalkyl group comprising three toeight carbon atoms, such as cyclopropyl group, cyclobutyl group,cyclopentyl group, cyclohexyl group, cycloheptyl group or cyclooctylgroup.

The “cycloalkenyl group having three to eight carbon atoms” used in thepresent invention represents a cycloalkenyl group comprising three toeight carbon atoms, such as cyclopropen-1-yl, cyclopropen-3-yl,cyclobuten-1-yl, cyclobuten-3-yl, 1,3-cyclobutadien-1-yl,cyclopenten-1-yl, cyclopenten-3-yl, cyclopenten-4-yl,1,3-cyclopentadien-1-yl, 1,3-cyclopentadien-2-yl,1,3-cyclopentadien-5-yl, cyclohexen-1-yl, cyclohexen-3-yl,cyclohexen-4-yl, 1,3-cyclohexadien-1-yl, 1,3-cyclohexadien-2-yl,1,3-cyclohexadien-5-yl, 1,4-cyclohexadien-3-yl, 1,4-cyclohexadien-1-yl,cyclohepten-1-yl, cyclohepten-3-yl, cyclohepten-4-yl, cyclohepten-5-yl,1,3-cyclohepten-2-yl, 1,3-cyclohepten-1-yl, 1,3-cycloheptadien-5-yl,1,3-cycloheptadien-6-yl, 1,4-cycloheptadien-3-yl,1,4-cycloheptadien-2-yl, 1,4-cycloheptadien-1-yl,1,4-cycloheptadien-6-yl, 1,3,5-cycloheptatrien-3-yl,1,3,5-cycloheptatrien-2-yl, 1,3,5-cycloheptatrien-1-yl,1,3,5-cycloheptatrien-7-yl, cycloocten-1-yl, cycloocten-3-yl,cycloocten-4-yl, cycloocten-5-yl, 1,3-cyclooctadien-2-yl,1,3-cyclooctadien-1-yl, 1,3-cyclooctadien-5-yl, 1,3-cyclooctadien-6-yl,1,4-cyclooctadien-3-yl, 1,4-cyclooctadien-2-yl, 1,4-cyclooctadien-1-yl,1,4-cyclooctadien-6-yl, 1,4-cyclooctadien-7-yl, 1,5-cyclooctadien-3-yl,1,5-cyclooctadien-2-yl, 1,3,5-cyclooctatrien-3-yl,1,3,5-cyclooctatrien-2-yl, 1,3,5-cyclooctatrien-1-yl,1,3,5-cyclooctatrien-7-yl, 1,3,6-cyclooctatrien-2-yl,1,3,6-cyclooctatrien-1-yl, 1,3,6-cyclooctatrien-5-yl or1,3,6-cyclooctatrien-6-yl group.

The “5 to 14-membered non-aromatic heterocyclic group” used in thepresent description refers to a monocyclic, bicyclic or tricyclic 5 to14-membered non-aromatic heterocyclic group and containing one or morehetero atoms selected from the group consisting of nitrogen atom, sulfuratom and oxygen atom. Specific examples of the group are pyrrolidinylgroup, piperidinyl group, piperazinyl group, pyrazolinyl group,morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group,dihydrofuryl group, dihydropyranyl group, imidazolinyl group, andoxazolinyl group. The non-aromatic heterocyclic group also includes agroup derived from pyridone ring, and a non-aromatic fused ring (e.g., agroup derived from phthalimide ring or succinimide ring).

The “aromatic cyclic hydrocarbon group having six to fourteen carbonatoms” and the “aryl” used in the present description represent anaromatic cyclic hydrocarbon group comprising six to fourteen carbonatoms and include monocyclic groups, as well as fused groups such asbicyclic groups and tricyclic groups. Specific examples of the groupinclude phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group,azulenyl group, heptalenyl group, biphenyl group, indacenyl group,acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenylgroup, anthracenyl group, cyclopentacyclooctenyl group, andbenzocyclooctenyl group.

The “5 to 14-membered aromatic heterocyclic group” and the “heteroaryl”used in the present description represent a monocyclic, bicyclic ortricyclic 5 to 14-membered aromatic heterocyclic group containing one ormore hetero atoms selected from nitrogen atom, sulfur atom and oxygenatom. Specific examples of the group include 1) a nitrogen-containingaromatic heterocyclic group such as pyrrolyl group, pyridyl group,pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group,tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolylgroup, benzimidazolyl group, indolyl group, isoindolyl group,indolizinyl group, purinyl group, indazolyl group, quinolyl group,isoquinolyl group, quinolizyl group, phthalazyl group, naphthyridinylgroup, quinoxalyl group, quinazolinyl group, cinnolinyl group,pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group,acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinylgroup, perimidinyl group, phenanthrolinyl group, phenacinyl group,imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinylgroup or pyrazolopyridinyl group; 2) a sulfur-containing aromaticheterocyclic group such as thienyl group or benzothienyl group; 3) anoxygen-containing aromatic heterocyclic group such as furyl group,pyranyl group, cyclopentapyranyl group, benzofuryl group orisobenzofuryl group; and 4) an aromatic heterocyclic group containingtwo or more different hetero atoms, such as thiazolyl group,isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group,phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinylgroup, oxazolyl group, isoxazolyl group, benzoxazolyl group, oxadiazolylgroup, pyrazolooxazolyl group, imidazothiazolyl group, thienofuranylgroup, furopyrrolyl group or pyridooxazinyl group.

The “aliphatic acyl group having two to seven carbon atoms” used in thepresent description represents an atomic group derived from an aliphaticcarboxyl group having two to seven carbon atoms by removing OH groupfrom its carboxyl group, and suitable examples thereof are acetyl group,propionyl group and butyroyl group.

The “arylacyl group” used in the present description represents acarbonyl group substituted with an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms, and the “heteroarylacyl group”represents a carbonyl group substituted with a 5 to 14-membered aromaticheterocyclic group. The “aromatic cyclic hydrocarbon group having six tofourteen carbon atoms” and the “5 to 14-membered aromatic heterocyclicgroup” as used herein have the same meanings as defined above.

Suitable examples of the “alkylsulfonyl group having one to six carbonatoms”, “alkenylsulfonyl group having two to six carbon atoms” and“alkynylsulfonyl group having two to six carbon atoms” used in thepresent description include methylsulfonyl group, ethylsulfonyl group,n-propylsulfonyl group, iso-propylsulfonyl group, n-butylsulfonyl group,t-butylsulfonyl group, vinylsulfonyl group, allylsulfonyl group,iso-propenylsulfonyl group, iso-pentenylsulfonyl group, andethynylsulfonyl group. Suitable examples of the “alkylsulfinyl grouphaving one to six carbon atoms”, “alkenylsulfinyl group having two tosix carbon atoms” and “alkynylsulfinyl group having two to six carbonatoms” used in the present description include methylsulfinyl group,ethylsulfinyl group, n-propylsulfinyl group, iso-propylsulfinyl group,n-butylsulfinyl group, t-butylsulfinyl group, vinylsulfinyl group,allylsulfinyl group, iso-propenylsulfinyl group, iso-pentenylsulfinylgroup, and ethynylsulfinyl group.

Examples of the “substituents” in the “amino group which may besubstituted” used in the present description represents one or twogroups selected from an alkyl group having one to six carbon atoms, analkenyl group having two to six carbon atoms, an alkynyl group havingtwo to six carbon atoms, an alkylsulfonyl group having one to six carbonatoms, an alkenylsulfonyl group having two to six carbon atoms,alkynylsulfonyl group having two to six carbon atoms, an alkylcarbonylgroup having one to six carbon atoms, an alkenylcarbonyl group havingtwo to six carbon atoms, an alkynylcarbonyl group having two to sixcarbon atoms, each of which may be substituted. In this connection, thesubstituents may be combined to form a 3 to 8-memberednitrogen-containing ring. Suitable examples of the “substituents” in thealkyl group having one to six carbon atoms, alkenyl group having two tosix carbon atoms, alkynyl group having two to six carbon atoms,alkylsulfonyl group having one to six carbon atoms, alkenylsulfonylgroup having two to six carbon atoms, alkynylsulfonyl group having twoto six carbon atoms, C₁₋₆ alkyl-carbonyl group, C₂₋₆ alkenyl-carbonylgroup and C₂₋₆ alkynyl-carbonyl group include a hydroxyl group, ahalogen atom, a nitrile group, an alkoxy group has iso-pentylaminogroup, neopentylamino group, n-hexylamino group, 1-methylpropylaminogroup, 1,2-dimethylpropylamino group, 2-ethylpropylamino group,1-methyl-2-ethylpropylamino group, 1-ethyl-2-methylpropylamino group,1,1,2-trimethylpropylamino group, 1-methylbutylamino group,2-methylbutylamino group, 1,1-dimethylbutylamino group,2,2-dimethylbutylamino group, 2-ethylbutylamino group,1,3-dimethylbutylamino group, 2-methylpentylamino group,3-methylpentylamino group, N,N-dimethylamino group, N,N-diethylaminogroup, N,N-di(n-propyl)amino group, N,N-di(iso-propyl)amino group,N,N-di(n-butyl)amino group, N,N-di(iso-butyl)amino group,N,N-di(t-butyl)amino group, N,N-di(n-pentyl)amino group,N,N-di(iso-pentyl)amino group, N,N-di(neopentyl)amino group,N,N-di(n-hexyl)amino group, N,N-di(1-methylpropyl)amino group, N,N-di(1,2-dimethylpropyl)amino group, N-methyl-N-ethylamino group,N-ethyl-N-(n-propyl)amino group, N-methyl-N-(i-propyl)amino group,vinylamino group, allylamino group, (1-propenyl)amino group,isopropenylamino group, (1-buten-1-yl)amino group, (1-buten-2-yl)aminogroup, (1-buten-3-yl)amino group, (2-buten-1-yl)amino group,(2-buten-2-yl)amino group, N,N-divinylamino group, N,N-diallylaminogroup, N,N-di(1-propenyl)amino group, N,N-isopropenylamino group,N-vinyl-N-allylamino group, ethynylamino group, 1-propynylamino group,2-propynylamino group, butynylamino group, pentynylamino group,hexynylamino group, N,N-diethynylamino group, N,N-(1-propynyl)aminogroup, N,N-(2-propynyl)amino group, N,N-dibutynylamino group,N,N-dipentynylamino group, N,N-dihexynylamino group, hydroxymethylaminogroup, 1-hydroxyethylamino group, 2-hydroxyethylamino group,3-hydroxy-n-propyl group, methylsulfonylamino group, ethylsulfonylaminogroup, n-propylsulfonylamino group, iso-propylsulfonylamino group,n-butylsulfonylamino group, t-butylsulfonylamino group,vinylsulfonylamino group, allylsulfonylamino group,iso-propenylsulfonylamino group, iso-pentenylsulfonylamino group,ethynylsulfonylamino group, methylcarbonylamino group,ethylcarbonylamino group, n-propylcarbonylamino group,iso-propylcarbonylamino group, n-butylcarbonylamino group,t-butylcarbonylamino group, vinylcarbonylamino group, allylcarbonylaminogroup, iso-propenylcarbonylamino group, iso-pentenylcarbonylamino group,and ethynylcarbonylamino group.

Examples of the “substituents” in the phrase “which may be substituted”used in the present description include a halogen atom such as fluorineatom, chlorine atom, bromine atom or iodine atom; a hydroxyl group; anitro group; a cyano group; an alkyl group having one to six carbonatoms such as methyl group, ethyl group, n-propyl group, iso-propylgroup, n-butyl group, iso-butyl group, sec-butyl group, t-butyl group,n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group,2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group,n-hexyl group or 1-methyl-2-ethylpropyl group; an alkenyl group havingtwo to six carbon atoms such as vinyl group, allyl group, 1-propenylgroup, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group,3-methyl-1-propenyl group, 2-methyl-2-propenyl group,3-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenylgroup, 1-pentenyl group, 1-hexenyl group, 1,3-hexadienyl group or1,6-hexadienyl group; an alkynyl group having two to six carbon atomssuch as ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynylgroup, 2-butynyl group, 3-butynyl group, 3-methyl-1-propynyl group,1-ethynyl-2-propynyl group, 2-methyl-3-propynyl group, 1-pentynyl group,1-hexynyl group, 1,3-hexadiynyl group or 1,6-hexadiynyl group; an alkoxygroup having one to six carbon atoms such as methoxy group, ethoxygroup, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxygroup, iso-butoxy group, sec-butoxy group, t-butoxy group, n-pentyloxygroup, iso-pentyloxy group, sec-pentyloxy group or n-hexyloxy group; analkenyloxy group having two to six carbon atoms such as vinyloxy group,allyloxy group, 1-propenyloxy group, 2-propenyloxy group orisopropenyloxy group; an alkynyloxy group having two to six carbon atomssuch as ethynyloxy group, 1-propynyloxy group or 2-propynyloxy group; analkylthio group having one to six carbon atoms such as methylthio group,ethylthio group, n-propylthio group, iso-propylthio group,sec-propylthio group, n-butylthio group, iso-butylthio group,sec-butylthio group or t-butylthio group; an alkenylthio group havingtwo to six carbon atoms such as vinylthio group, allylthio group,1-propenylthio group or 2-propenylthio group; an alkynylthio grouphaving two to six carbon atoms such as ethynylthio group, 1-propynylthiogroup or 2-propynylthio group; an aliphatic acyl group having two toseven carbon atoms such as acetyl group, propionyl group or butyroylgroup; carbamoyl group; an arylacyl group; a heteroarylacyl group; anamino group; an alkylsulfonyl group having one to six carbon atoms, analkenylsulfonyl group having two to six carbon atoms, an alkynylsulfonylgroup having two to six carbon atoms, an alkylsulfinyl group having oneto six carbon atoms, an alkenylsulfinyl group having two to six carbonatoms or an alkynylsulfinyl group having two to six carbon atoms, suchas methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group,iso-propylsulfonyl group, n-butylsulfonyl group, t-butylsulfonyl group,vinylsulfonyl group, allylsulfonyl group, iso-propenylsulfonyl group,iso-pentenylsulfonyl group, ethynylsulfonyl group, methylsulfinyl group,ethylsulfinyl group, n-propylsulfinyl group, iso-propylsulfinyl group,n-butylsulfinyl group, t-butylsulfinyl group, vinylsulfinyl group,allylsulfinyl group, iso-propenylsulfinyl group, iso-pentenylsulfinylgroup or ethynylsulfinyl group; a formyl group, a cycloalkyl grouphaving three to eight carbon atoms such as cyclopropyl group, cyclobutylgroup, cyclopentyl group, cyclohexyl group, cycloheptyl group orcyclooctyl group; a cycloalkenyl group having three to eight carbonatoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenylgroup; a 5 to 14-membered non-aromatic heterocyclic group, such aspyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinylgroup, imidazolyl group, pyrazolidyl group, imidazolidyl group,morpholinyl group, tetrahydrofuryl group, tetrahydropyranyl group,pyrrolinyl group, dihydrofuryl group, dihydropyranyl group, imidazolinylgroup, oxazolinyl group, a group derived from pyridone ring, and a groupderived from phthalimide ring or succinimide ring; an aromatic cyclichydrocarbon group having six to fourteen carbon atoms such as phenylgroup, indenyl group, 1-naphthyl group, 2-naphthyl group, biphenyl groupor indacenyl group; a 5 to 14-membered aromatic heterocyclic group, suchas pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolylgroup, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolylgroup, isoindolyl group, indolizinyl group, purinyl group, indazolylgroup, quinolyl group, isoquinolyl group, quinolizinyl group,phthalazinyl group, naphthyridinyl group, quinoxalyl group, quinazolinylgroup, cinnolinyl group, pteridinyl group, imidazotriazinyl group,pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group,carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinylgroup, phenazinyl group, imidazopyridyl group, imidazopyrimidinyl group,pyrazolopyridyl group, pyrazolopyridyl group, thienyl group,benzothienyl group, furyl group, pyranyl group, cyclopentapyranyl group,benzofuryl group, isobenzofuryl group, thiazolyl group, isothiazolylgroup, benzothiazolyl group, benzothiadiazolyl group, phenothiazinylgroup, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolylgroup, isoxazolyl group, benzoxazolyl group, oxadiazolyl group,pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl group,furopyrrolyl group or pyridooxazinyl group. Each of these substituentsmay be further substituted.

In the formula (I), suitable examples of the “substituents” in the“carbamoyl group which may be substituted” are groups selected from analkyl group having one to six carbon atoms which may be substituted, analkenyl group having two to six carbon atoms which may be substituted,an alkynyl group having two to six carbon atoms which may besubstituted, a cycloalkyl group having three to eight carbon atoms whichmay be substituted, a cycloalkenyl group having three to eight carbonatoms which may be substituted, an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted, and a 5 to14-membered aromatic heterocyclic group which may be substituted. Thenitrogen atom of the carbamoyl group may be substituted with one or twogroups selected from the above group of substituents. The substituentsmay be combined to form a 3 to 14-membered nitrogen-containing ring,such as pyrrolidyl group, pyrrolinyl group, piperidyl group, piperazinylgroup, imidazolyl group, pyrazolidyl group, imidazolidyl group,morpholinyl group, tetrahydropyranyl group, aziridinyl group, oxiranylgroup, oxathiolanyl group, phthalimidyl group, succinimidyl group,pyrrolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group,pyrazinyl group or pyrazolyl group. In addition, the nitrogen-containingring may be substituted.

In the formula (I), a preferred group in R¹ and/or R² is notspecifically limited, of which a hydrogen atom, an alkyl group havingone to six carbon atoms and an aliphatic acyl group having two to sevencarbon atoms, each of which may be substituted, are more preferred, anda hydrogen atom is typically preferred.

In the formula (I), a preferred group in R³ is not specifically limited,of which a hydrogen atom, an alkyl group having one to six carbon atoms,an alkenyl group having two to six carbon atoms or an alkynyl grouphaving two to six carbon atoms, each of which may be substituted, ismore preferred, and a hydrogen atom, methyl group, ethyl group, n-propylgroup or allyl group is typically preferred.

In the formula (I), R⁴ represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted, a 5 to14-membered non-aromatic heterocyclic group having one or moreunsaturated bonds or a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted, and suitable examples thereof are an aromaticcyclic hydrocarbon group having six to fourteen carbon atoms such asphenyl group or naphthyl group; a 5 to 14-membered non-aromaticheterocyclic group, such as pyrrolidinyl group, pyrrolinyl group,piperidinyl group, piperazinyl group, imidazolinyl group, pyrazolidinylgroup, imidazolidinyl group, morpholinyl group, tetrahydropyranyl group,aziridinyl group, oxiranyl group, oxathiolanyl group,2-oxo-1,2-dihydropyridinyl group or 6-oxo-1,6-dihydropyridyl group whichmay be substituted on its nitrogen atom; or a 5 to 14-membered aromaticheterocyclic group, such as pyrrolyl group, pyridyl group, pyridazinylgroup, pyrimidinyl group, pyrazinyl group, pyrazolyl group, imidazolylgroup, indolyl group, isoindolyl group, indolizinyl group, quinolylgroup, isoquinolyl group, quinolizinyl group, phthalazinyl group,naphthyridyl group, quinoxalyl group, quinazolyl group, imidazotriazinylgroup, pyrazinopyridazinyl group, thienyl group, benzothienyl group,furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group,isobenzofuryl group, thiazolyl group, isothiazolyl group, benzothiazolylgroup, benzothiadiazolyl group, phenothiazyl group, isoxazolyl group,pyrazolooxazolyl group, imidazothiazolyl group, thienofuryl group,furopyrrolyl group or pyridooxazinyl group. Each of these groups may befurther substituted. More preferred examples of R⁴ include groupsrepresented by the formulae:

each of which may be substituted. When the 6-oxo-1,6-dihydropyridylgroup or 2-oxo-1,2-dihydropyridyl group has a substituent, thesubstituent may also be combined with the nitrogen atom.

In the formula (I), R⁵ refers to an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms or a 5 to 14-membered aromaticheterocyclic group, each of which may be substituted, and suitableexamples thereof include an aromatic cyclic hydrocarbon group having sixto fourteen carbon atoms such as phenyl group or naphthyl group, or a 5to 14-membered aromatic heterocyclic group, such as pyrrolyl group,pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group,pyrazolyl group, imidazolyl group, indolyl group, isoindolyl group,indolizinyl group, quinolyl group, isoquinolyl group, quinolizinylgroup, phthalazinyl group, naphthyridyl group, quinoxalyl group,quinazolyl group, imidazotriazinyl group, pyrazinopyridazinyl group,thienyl group, benzothienyl group, furyl group, pyranyl group,cyclopentapyranyl group, benzofuryl group, isobenzofuryl group,thiazolyl group, isothiazolyl group, benzothiazolyl group,benzothiadiazolyl group, phenothiazyl group, isoxazolyl group,pyrazolooxazolyl group, imidazothiazolyl group, thienofuryl group,furopyrrolyl group or pyridooxazinyl group. Each of these groups may besubstituted. More preferred examples of R⁵ include groups represented bythe formulae:

each of which may be substituted.

In the “substituents” in the “aromatic cyclic hydrocarbon group havingsix to fourteen carbon atoms which may be substituted” and the “5 to14-membered aromatic heterocyclic group which may be substituted”, (1)preferred examples are one or more groups selected from a hydroxylgroup, a halogen atom, a cyano group, a nitro group, an alkyl grouphaving one to six carbon atoms which may be substituted, an alkenylgroup having two to six carbon atoms which may be substituted, analkynyl group having two to six carbon atoms which may be substituted,an alkoxy group having one to six carbon atoms which may be substituted,an alkenyloxy group having two to six carbon atoms which may besubstituted, an alkylthio group having one to six carbon atoms which maybe substituted, an alkenylthio group having two to six carbon atomswhich may be substituted, an alkynylthio group having two to six carbonatoms which may be substituted, a substituted carbonyl group, an aminogroup which may be substituted, an alkylsulfonyl group having one to sixcarbon atoms which may be substituted, an alkenylsulfonyl group havingtwo to six carbon atoms which may be substituted, an alkynylsulfonylgroup having two to six carbon atoms which may be substituted, analkylsulfinyl group having one to six carbon atoms which may besubstituted, an alkenylsulfinyl group having two to six carbon atomswhich may be substituted, an alkynylsulfinyl group having two to sixcarbon atoms which may be substituted, a formyl group, a cycloalkylgroup having three to eight carbon atoms which may be substituted, acycloalkenyl group having three to eight carbon atoms which may besubstituted, a 5 to 14-membered non-aromatic heterocyclic group whichmay be substituted, an aromatic cyclic hydrocarbon group having six tofourteen carbon atoms which may be substituted and a 5 to 14-memberedaromatic heterocyclic group which may be substituted; (2) morepreferably, one or more groups selected from (1) a hydroxyl group, (2) ahalogen atom, (3) a cyano group, (4) a nitro group, (5) an alkyl grouphaving one to six carbon atoms, an alkenyl group having two to sixcarbon atoms or an alkynyl group having two to six carbon atoms, each ofwhich may be substituted with one or more groups selected from (i) ahydroxyl group, (ii) a cyano group, (iii) a halogen atom, (iv) analkylamino group having one to six carbon atoms, (v) a di(C₁₋₆alkyl)amino group, (vi) a C₂₋₆ alkenylamino group, (vii) a di(C₂₋₆alkenyl)amino group, (viii) an alkynylamino group having two to sixcarbon atoms, (ix) a di(C₂₋₆ alkynyl)amino group, (x) an N—C₁₋₆alkyl-N—C₂₋₆ alkenylamino group, (xi) an N—C₁₋₆ alkyl-N—C₂₋₆alkynylamino group, (xii) an N—C₂₋₆ alkenyl-N—C₂₋₆ alkynylamino group,(xiii) an aralkyloxy group, (xiv) a t-butyldimethylsilyloxy (TBDMS-oxy)group, (xv) a C₁₋₆ alkylsulfonylamino group, (xvi) a C₁₋₆alkylcarbonyloxy group, (xvii) a C₂₋₆ alkenylcarbonyloxy group, (xviii)a C₂₋₆ alkynylcarbonyloxy group, (xix) an N—C₁₋₆ alkylcarbamoyl group,(xx) an N—C₂₋₆ alkenylcarbamoyl group and (xxi) an N—C₁₋₆alkynylcarbamoyl group, (6) an alkoxy group having one to six carbonatoms, an alkenyloxy group having two to six carbon atoms or analkynyloxy group having two to six carbon atoms, each of which may besubstituted with one or more groups selected from (i) an alkylaminogroup having one to six carbon atoms, (ii) an aralkyloxy group and (iii)a hydroxyl group, (7) an alkylthio group having one to six carbon atoms,an alkenylthio group having two to six carbon atoms or an alkynylthiogroup having two to six carbon atoms, each of which may be substitutedwith one or more groups selected from (i) a hydroxyl group, (ii) anitrile group, (iii) a halogen atom, (iv) an alkylamino group having oneto six carbon atoms, (v) an aralkyloxy group, (vi) a TBDMS-oxy group,(vii) a C₁₋₆ alkylsulfonylamino group, (viii) a C₁₋₆ alkylcarbonyloxygroup and (ix) a C₁₋₆ alkylcarbamoyl group, (8) carbonyl groupsubstituted with a group selected from (i) an alkoxy group having one tosix carbon atoms, (ii) an amino group, (iii) an alkylamino group havingone to six carbon atoms, (iv) a di(C₁₋₆ alkyl)amino group, (v) analkenylamino group having two to six carbon atoms, (vi) a di(C₂₋₆alkenyl)amino group, (vii) an alkynylamino group having two to sixcarbon atoms, (vii) a di(C₂₋₆ alkynyl)amino group, (viii) an N—C₁₋₆alkyl-N—C₂₋₆ alkenylamino group, (ix) an N—C₁₋₆ alkyl-N—C₂₋₆alkynylamino group and (x) an N—C₂₋₆ alkenyl-N—C₂₋₆ alkynylamino group,(9) an amino group which may be substituted with one or two groupsselected from (i) an alkyl group having one to six carbon atoms, (ii) analkenyl group having two to six carbon atoms, (iii) an alkynyl grouphaving two to six carbon atoms, (iv) an alkylsulfonyl group having oneto six carbon atoms, (v) an alkenylsulfonyl group having two to sixcarbon atoms, (vi) an alkynylsulfonyl group having two to six carbonatoms, (vii) a C₁₋₆ alkylcarbonyl group, (viii) a C₂₋₆ alkenylcarbonylgroup and (ix) a C₂₋₆ alkynylcarbonyl group, (10) an alkylsulfonyl grouphaving one to six carbon atoms, (11) an alkenylsulfonyl group having twoto six carbon atoms, (12) an alkynylsulfonyl group having two to sixcarbon atoms, (13) an alkylsulfinyl group having one to six carbonatoms, (14) an alkenylsulfinyl group having two to six carbon atoms,(15) an alkynylsulfinyl group having two to six carbon atoms, (16) aformyl group, (17) a cycloalkyl group having three to eight carbon atomsor cycloalkenyl group having three to eight carbon atoms, each of whichmay be substituted with one or more groups selected from (i) a hydroxylgroup, (ii) a halogen atom, (iii) a nitrile group, (iv) an alkyl grouphaving one to six carbon atoms, (v) an alkoxy group having one to sixcarbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii) an aralkylgroup, (18) a 5 to 14-membered non-aromatic heterocyclic group which maybe substituted with one or more groups selected from (i) a hydroxylgroup, (ii) a halogen atom, (iii) a nitrile group, (iv) an alkyl grouphaving one to six carbon atoms, (v) an alkoxy group having one to sixcarbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkyl group and (vii) an aralkylgroup, (19) an aromatic cyclic hydrocarbon group having six to fourteencarbon atoms which may be substituted with one or more groups selectedfrom (i) a hydroxyl group, (ii) a halogen atom, (iii) a nitrile group,(iv) an alkyl group having one to six carbon atoms, (v) an alkoxy grouphaving one to six carbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkyl group and(vii) an aralkyl group, and (20) a 5 to 14-membered aromaticheterocyclic group which may be substituted with one or more groupsselected from (i) a hydroxyl group, (ii) a halogen atom, (iii) a nitrilegroup, (iv) an alkyl group having one to six carbon atoms, (v) an alkoxygroup having one to six carbon atoms, (vi) a C₁₋₆ alkoxy-C₁₋₆ alkylgroup and (vii) an aralkyl group; and (3) most preferably, one or moregroups selected from a hydroxyl group, a halogen atom (e.g., fluorineatom, chlorine atom bromine atom or iodine atom), a cyano group, a nitrogroup, an alkyl group having one to six carbon atoms (e.g., methylgroup, ethyl group, n-propyl group, iso-propyl group, n-butyl group,iso-butyl group, t-butyl group, n-pentyl group, i-pentyl group,neopentyl group or n-hexyl group), an alkenyl group having two to sixcarbon atoms (e.g., vinyl group, allyl group, 1-propenyl group orisopropenyl group), an alkynyl group having two to six carbon atoms(e.g., ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group,pentynyl group or hexynyl group), an alkoxy group having one to sixcarbon atoms (e.g., methoxy group, ethoxy group, n-propoxy group,iso-propoxy group or n-butoxy group) and an alkenyloxy group having twoto six carbon atoms (e.g., vinyloxy group, allyloxy group, 1-propenyloxygroup or isopropenyloxy group).

Preferred embodiments of the compound represented by the formula (I)according to the present invention, a salt thereof or a solvate of themare not specifically limited, of which more preferred embodiments arecompounds wherein R⁴ is 4-pyridyl group which may have one or twosubstituents, a salt thereof or a solvate of them.

The “salt” used in the present description is a salt formed from thecompound according to the present invention, of which apharmacologically acceptable salt is preferred. Preferred examplesthereof are a hydrohalogenic acid salt such as hydrofluoride,hydrochloride, hydrobromide or hydroiodide; an inorganic acid salt suchas sulfate, nitrate, perchlorate, phosphate, carbonates orhydrogencarbonate; an organic carboxylic acid salt such as acetate,trifluoroacetate, oxalate, maleate, tartrate, fumarate or citrate; anorganic sulfonic acid salt such as methanesulfonate,trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate or camphorsulfonate; an amino acid salt such asaspartate or glutamate; a quaternary amine salt; an alkali metal saltsuch as sodium salt or potassium salt; an alkaline earth metal salt suchas magnesium salt or calcium salt. More preferred examples of the“pharmacologically acceptable salt” are hydrochloride and oxalate.

The “solvate” used in the present description is a solvate of thecompound according to the present invention or a salt thereof and is notspecifically limited. Preferably, the solvate is a hydrate, a solvatewith an alcohol such as methanol, ethanol, propanol, or isopropanol, asolvate with an ester such as ethyl acetate, a solvate with an ethersuch as methyl ether, ethyl ether or THF (tetrahydrofuran) or a solvatewith DMF (dimethylformamide), of which a hydrate or a solvate with analcohol such as methanol or ethanol is more preferred. A solvent forconstituting the solvate is preferably a pharmacologically acceptablesolvent.

Production Process

Typical production processes for the compounds represented by theformula (I) and the formula (IV) of the present invention will beillustrated below. The “room temperature” as used hereinafter representsa temperature from about 0° C. to about 40° C.

In the formula, Ar^(1a) and R^(1a) are the same as or different fromeach other and each represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andR^(2a) and R^(3a) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic cyclic hydrocarbon group having six to fourteen carbon atomswhich may be substituted, or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted.

Step A-1: In this process, the compound (A1) is subjected todehydration-condensation with an aldehyde compound in the presence of abase, to give the compound (A2). The base for use in the reaction ispreferably an alkali metal alkoxide, such as sodium methoxide, sodiumethoxide or potassium t-butoxide, and an alkali metal carbonate such aspotassium carbonate or sodium carbonate may be also used. The reactionis performed in a solvent which does not adversely affect the reactionand dissolves the starting compounds and intermediates therein to someextent, such as ethanol, methanol, tetrahydrofuran, dichloromethane,chloroform, N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, or a mixture of these solvents. The reaction is performed at0° C. to 120° C.Step A-2: In this process, the compound (A2) prepared in Process A-1 isreacted and cyclized with a guanidine derivative in the presence of abase and is aromatized with an oxidizing agent, to give the pyrimidinonederivative (A3) according to the present invention. The base for use inthe cyclization is preferably an alkali metal alkoxide such as sodiummethoxide, sodium ethoxide or potassium t-butoxide, and an alkali metalcarbonate such as potassium carbonate or sodium carbonate may be alsoused. The oxidizing agent for the aromatization includes, for example, amanganese compound such as activated manganese dioxide; a quinone suchas 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; and sulfur. The solventfor use herein is not specifically limited, as long as it does notadversely affect the reaction and can dissolve the starting compoundsand intermediates to some extent, and ethanol, methanol,tetrahydrofuran, dichloromethane, chloroform, N,N-dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide, or a mixture of these solventsare preferred. The reaction is performed at 0° C. to 120° C.

In the formula, Ar^(1b) and R^(1b) are the same as or different fromeach other and each represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andX^(b) represents a halogen atom, an alkylsulfonyloxy group or anarylsulfonyloxy group. This process is another synthetic process of thecompound (A2) in Process A-1 of Production Process A. That is, thecompound (B1) is reacted with a diester of cyanomethylphosphonic acid inthe presence of a base and a palladium catalyst and is subjected todephosphorylation-condensation with an aldehyde compound, to give thecompound (B2). A suitable base for use in the reaction varies dependingon, for example, the starting materials and the solvents, is notspecifically limited, as long as it does not adversely affect thereaction, and is preferably sodium hydride. A suitable palladiumcatalyst for use herein varies depending on, for example, the startingmaterials and the solvent, is not specifically limited, as long as itdoes not adversely affect the reaction, and preferred examples thereofare tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(0) andtris(dibenzylideneacetone)dipalladium(0). A suitable reaction solventfor use herein varies depending on, for example, the starting materialsand the reagent, is not specifically limited, as long as it does notadversely affect the reaction and can dissolve the starting materialstherein to some extent, and is preferably an ether such asdimethoxyethane, diethyl ether or tetrahydrofuran. The reaction isperformed at 0° C. to 120° C.

In the formula, Ar^(1c) and R^(1c) are the same as or different fromeach other and each represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; R^(2c)and R^(3c) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic cyclic hydrocarbon group having six to fourteen carbon atomswhich may be substituted or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; and X^(c) represents an alkyl grouphaving one to six carbon atoms.

Step C-1: In this process, the compound (C1) is subjected todehydration-condensation with an aldehyde compound using a carboxylicanhydride in the presence of a base, to give the compound (C2). Asuitable base for use in the reaction varies depending on the startingmaterials and the solvents, is not specifically limited, as long as itdoes not adversely affect the reaction and includes, for example, anamine such as triethylamine, pyrrolidine, piperidine ordiisopropylethylamine. As the carboxylic anhydride, acetic anhydride ispreferred. The reaction is performed at a temperature from roomtemperature to 120° C.Step C-2: In this process, the compound (C2) prepared in Process C-1 isreacted with a guanidine derivative in the presence of a base and isthen aromatized using an oxidizing agent, to give the pyrimidinonederivative (C3) of the present invention. A suitable base for use in thereaction varies depending on the starting materials and the solvents, isnot specifically limited, as long as it does not adversely affect thereaction, and includes an alkali metal alkoxide such as sodiummethoxide, sodium ethoxide or potassium t-butoxide, as well as an alkalimetal carbonate such as potassium carbonate or sodium carbonate. Asuitable oxidizing agent for use in the reaction varies depending on thestarting materials and the solvent, is not specifically limited, as longas it does not adversely affect the reaction and includes, for example,a manganese compound such as activated manganese dioxide; a quinone suchas 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; and sulfur. The reactionis performed in a solvent that does not adversely affect the reactionand dissolves the starting compounds and intermediates to some extent,such as ethanol, methanol, tetrahydrofuran, dichloromethane, chloroform,N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or amixture of these solvents. The reaction is performed at 0° C. to 120° C.

In the formula, Ar^(1d) and R^(1d) are the same as or different fromeach other and each represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; andR^(2d) represents an alkyl group having one to six carbon atoms whichmay be substituted, an alkenyl group having two to six carbon atomswhich may be substituted or an alkynyl group having two to six carbonatoms which may be substituted. In this process, the nitrogen atom atthe 3-position or the amino group at the 2-position of pyrimidinenucleus of the pyrimidinone derivative (D1) prepared in ProductionProcess A or C is alkylated. The reaction is performed, for example, byreacting the compound with an alkyl halide compound in a solvent in thepresence of a base.

A suitable base for use herein varies depending on the startingmaterials and the solvent, is not specifically limited, as long as itdoes not adversely affect the reaction and is preferably sodium hydride,sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, sodiumcarbonate or potassium carbonate. A suitable solvent for use hereinvaries depending on the starting materials and the reagent, is notspecifically limited, as long as it dissolves the starting materials tosome extent, and preferred examples thereof are an alcohol such asmethanol or ethanol; an ether such as tetrahydrofuran, dioxane,dimethoxyethane or diethylene glycol dimethyl ether; as well asN,N-dimethylformamide, dimethyl sulfoxide, 1-methylpyrrolidinone. Thereaction is performed at a temperature from 0° C. to 100° C.

In the formula, Ar^(1e) represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted; R^(1e)and R^(2e) are the same as or different from each other and eachrepresents a hydrogen atom, an alkyl group having one to six carbonatoms which may be substituted, an alkenyl group having two to sixcarbon atoms which may be substituted, an alkynyl group having two tosix carbon atoms which may be substituted, a cycloalkyl group havingthree to eight carbon atoms which may be substituted, a cycloalkenylgroup having three to eight carbon atoms which may be substituted, a 5to 14-membered non-aromatic heterocyclic group which may be substituted,an aromatic cyclic hydrocarbon group having six to fourteen carbon atomswhich may be substituted, or a 5 to 14-membered aromatic heterocyclicgroup which may be substituted; R^(3e) and R^(4e) are the same as ordifferent from each other and each represents a hydrogen atom, an alkylgroup having one to six carbon atoms which may be substituted, analkenyl group having two to six carbon atoms which may be substituted,or an alkynyl group having two to six carbon atoms which may besubstituted; the ring A^(e) represents pyridinyl group, pyrimidinylgroup, pyrazinyl group or pyridazinyl group; and the ring A′ representsdihydrooxopyridinyl group, dihydrooxopyrimidinyl group,dihydrooxopyrazinyl group or dihydrooxopyridazinyl group. In thisprocess, the alkoxy group of the 5-(α-alkoxy-nitrogen-containingheteroaryl)pyrimidinone (E1) is hydrolyzed, to give5-(α-oxo-nitrogen-containing heterocyclyl)pyrimidinone (E2) of to thepresent invention. The reaction is performed in an aqueous solution of amineral acid such as hydrochloric acid, hydrobromic acid or sulfuricacid or a mixture of the aqueous solution of the mineral acid withacetic acid at a temperature from room temperature to 100° C.

In the formula, Ar^(1e), R^(1e), R^(2e), R^(3e) and the ring A′ have thesame meanings as defined in Production Process E; R^(6f) represents, forexample, an alkyl group having one to six carbon atoms which may besubstituted, an alkenyl group having two to six carbon atoms which maybe substituted or an alkynyl group having two to six carbon atoms whichmay be substituted; and X^(f) represents a halogen atom, analkylsulfonyloxy group or an arylsulfonyloxy group. In this process, thecompound (F2) having a substituent introduced into the nitrogen atom onthe ring A′ of the present invention can be prepared by reactingcompound (F1) with an alkyl halide compound and so on in a solvent inthe presence of base. A suitable base for use herein varies depending onthe starting materials and the solvent, is not specifically limited, aslong as it does not adversely affect the reaction and includes sodiumhydride, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, sodium carbonate or potassium carbonate. A suitablesolvent for use herein varies depending on the starting materials andthe reagent, is not specifically limited, as long as it does notadversely affect the reaction and dissolves the starting materials tosome extent, and includes an alcohol such as methanol or ethanol; anether such as tetrahydrofuran, dioxane, dimethoxyethane or diethyleneglycol dimethyl ether; as well as N,N-dimethylformamide, dimethylsulfoxide or 1-methylpyrrolidinone. The reaction is generally performedat a temperature from 0° C. to 100° C.

In the formula, Ar^(1e), R^(1e), R^(2e), R^(3e) and the ring A′ have thesame meanings as defined in Production Process E; and R^(6g) representsan aromatic cyclic hydrocarbon group having six to fourteen carbon atomswhich may be substituted, a 5 to 14-membered aromatic heterocyclic groupwhich may be substituted or an alkenyl group having two to six carbonatoms which may be substituted. The compound (G2) according to thepresent invention can be prepared by reacting the compound (G1) with anarylboron reagent, heteroarylboron reagent or alkenylboron reagent in asolvent in the presence of a base and a copper catalyst. A suitable basefor use in the reaction varies depending on the starting materials andthe solvent, is not specifically limited, as long as it does notadversely affect the reaction, and is preferably a tertiary amine suchas pyridine, diisopropylethylamine or triethylamine. A suitable coppercatalyst for use herein varies depending on the starting materials andthe solvent, is not specifically limited, as long as it does notadversely affect the reaction, is preferably a divalent copper compoundsuch as cupric acetate, cupric bromide or cupric sulfate and is morepreferably cupric acetate. A suitable solvent for use herein variesdepending on the starting materials and the reagent, is not specificallylimited, as long as it does not adversely affect the reaction anddissolves the starting materials to some extent, and is preferably, forexample N,N-dimethylformamide, tetrahydrofuran, ethyl acetate ordichloromethane. The reaction temperature is preferably from 0° C. to120° C.

Typical examples of the production processes for the compounds (I)according to the present invention have been illustrated above. Thematerial compounds used in the production of the compounds of thepresent invention may form salts and/or solvates and are notspecifically limited, as long as they do not adversely affect thereaction. When the compounds (I) according to the present invention areobtained as free compounds, they can be converted into possible salts ofthe above-mentioned compounds (I) according to a conventional procedure.Various isomers such as geometrical isomers, optical isomers based on anasymmetric carbon, rotational isomers, stereoisomers, and tautomersobtained as the compounds (I) according to the present invention can bepurified and isolated according to a conventional separation means. Suchseparation means include, for example, recrystallization, diastereomericsalt method, enzymatic resolution, and a variety of chromatography suchas thin layer chromatography, column chromatography or gaschromatography.

The compounds represented by the formula (I) according to the presentinvention, salts thereof or solvates of them can be formulated intopharmaceutical preparations as intact or as a mixture with, for example,a known pharmacologically acceptable carrier according to a conventionalprocedure. Preferred dosage forms are tablets, powders, subtle granules,granules, coated tablets, capsules, syrups, troches, inhalants,suppositories, injections, ointments, ophthalmic ointments, eye drops,nasal drops, ear drops, cataplasms, and lotions. In the formulation,generally used fillers, binders, disintegrators, lubricants, coloringagents, and flavoring agents, as well as stabilizers, emulsifiers,absorbefacients, surfactants, pH adjusting agents, antiseptics, andantioxidants according to necessity can be used. They can be formulatedaccording to a conventional procedure using components generally used asraw materials for pharmaceutical preparations. Examples of suchcomponents include (1) animal and vegetable oils such as soybean oil,beef tallow and synthetic glycerides; (2) hydrocarbons such as liquidparaffins, squalane and solid paraffins; (3) ester oils such asoctyldodecyl myristate and isopropyl myristate; (4) higher alcohols suchas cetostearyl alcohol and behenyl alcohol; (5) silicone resins; (6)silicone oils; (7) surfactants such as polyoxyethylene fatty acidesters, sorbitan fatty acid esters, glycerin fatty acid esters,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenatedcastor oils and polyoxyethylene-polyoxypropylene block copolymers; (8)water-soluble polymers such as hydroxyethyl cellulose, poly(acrylicacid)s, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidoneand methylcellulose; (9) lower alcohols such as ethanol and isopropanol;(10) polyhydric alcohols such as glycerol, propylene glycol, dipropyleneglycol and sorbitol; (11) sugars such as glucose and sucrose; (12)inorganic powders such as silicic anhydride, magnesium aluminiumsilicate and aluminium silicate; and (13) purified water. 1) The fillersinclude, for example, lactose, corn starch, sucrose, glucose, mannitol,sorbitol, crystalline cellulose and silicon dioxide; 2) the bindersinclude, for example, polyvinyl alcohol, polyvinyl ether,methylcellulose, ethylcellulose, gum arabic, gum tragacanth, gelatin,shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene blockpolymers, meglumine, calcium citrate, dextrin and pectin; 3) thedisintegrators include, for example, starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium hydrogencarbonate,calcium citrate, dextrin, pectin and carboxymethylcellulose calcium; 4)the lubricants include, for example, magnesium stearate, talc,polyethylene glycol, silica, and hardened vegetable oils; 5) thecoloring agents can be any coloring agents which are approved to add topharmaceutical preparations; 6) the flavoring agents include, forexample, cocoa powder, menthol, aromatic powder (empasm), peppermintoil, camphol (borneol) and cinnamon powder; and 7) the antioxidants canbe any antioxidants which are approved to add to pharmaceuticalpreparations, such as ascorbic acid and α-tocopherol.

1) The oral preparation is produced by mixing the compound according tothe present invention, a salt thereof or a solvate of them with afiller, and if necessary, a binder, disintegrator, lubricant, coloringagent, flavoring agent, and other components, and formulating themixture according to a conventional procedure into, for example, apowder, subtle granules, granules, tablet, coated tablet or capsules. 2)The tablets and granules can be appropriately coated with, for example,sugar or gelatin according to necessity. 3) The liquid formulations suchas syrups, injection preparations or eye drops can be prepared accordingto a conventional procedure by adding a pH adjusting agent, solubilizer,and isotonizing agent, and if necessary, a solubilizing agent,stabilizer, buffer, suspending agent, antioxidant, and other components.The liquid formulations can also be formed into freeze-dried products.The injections can be administered intravenously, subcutaneously and/orintramuscularly. Preferred examples of the suspending agents aremethylcellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic,powdered tragacanth, carboxymethylcellulose sodium and polyoxyethylenesorbitan monolaurate; preferred examples of the solubilizers arepolyoxyethylene hydrogenated caster oil, polysorbate 80, nicotinamideand polyoxyethylene sorbitan monolaurate; preferred examples of thestabilizers are sodium sulfite, sodium metasulfite and ether; preferredexamples of the preservatives are methyl p-hydroxybenzoate, ethylp-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. 4) Theexternal preparations can be produced according to a conventionalprocedure not specifically limited. Base materials for use herein can beany raw materials generally used in, for example, pharmaceuticalpreparations, quasi drugs and cosmetics. Such raw materials include, forexample, animal and vegetable oils, mineral oils, ester oils, waxes,higher alcohols, fatty acids, silicone oils, surfactants, phospholipids,alcohols, polyhydric alcohols, water-soluble polymers, clay minerals,and purified water. Where necessary, any of pH adjusting agents,antioxidants, chelating agents, antiseptics and antimolds, coloringagents, flavors, and others can be added. In addition, components havingdifferentiation-inducing action, blood-flow accelerators, bactericides,anti-inflammatory agents, cell activators, vitamins, amino acids,humectants, keratolytic agents, and other components can be addedaccording to necessity.

The dose of the pharmaceutical preparation according to the presentinvention varies depending on the degree of symptom, age, sex, bodyweight, administration mode, type of the salt, difference in sensibilityto the drug, concrete type of the disease and other factors. Generally,the pharmaceutical preparation may be administered to an adult in one toseveral divided doses at a daily dose of about 30 μg to about 10 g,preferably 100 μg to 5 g, and more preferably 100 μg to 100 mg for oraladministration, or about 30 μg to about 1 g, preferably 100 μg to 500mg, and more preferably 100 μg to 30 mg for injection administration.

The present invention can provide novel pyrimidone compounds. Thecompounds according to the present invention, salts thereof or solvatesof them have excellent antagonism against adenosine receptors (adenosineA₁, A_(2A), A₂₃ or A₃ receptor) and are specifically excellent as anantagonist against the adenosine A₂ receptors, specifically against theadenosine A_(2B) receptor. They are useful as an agent for treating orpreventing a disease to which the adenosine receptors (adenosine A₁,A_(2A), A_(2B) or A₃ receptor) relate and a disease against which anantagonist of the receptor is efficacious. They are useful as an agentfor treating, preventing or improving, for example, constipation,irritable bowel syndrome, constipation accompanying irritable bowelsyndrome, organic constipation, constipation accompanyingenteroparalytic ileus, constipation accompanying congenital digestivetract dysfunction, constipation accompanying ileus, diabetes mellitus,diabetic complications, diabetic retinopathy, obesity or asthma and arealso useful as, for example, a hypoglycemic agent, agent forameliorating glucose intolerance, insulin sensitizer, antihypertensivedrug, diuretic agent, agent for treating osteoporosis, agent fortreating Parkinson's disease, agent for treating Alzheimer's disease,agent for treating an inflammatory bowel disease or agent for treatingCrohn's disease.

EXAMPLES

The following Referential Examples, Examples and Test Examples areillustrative, and the compounds of the present invention are under nocircumstances restricted by the following examples. Those skilled in theart can modify not only the following Examples but also the claimsaccording to the present description in various ways to exploit to thefull of the present invention, and such modifications and variations arealso included within the scope of the appended claims relating to thepresent description.

Referential Example 1 Ethyl(E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenoate

A solution of ethyl 4-pyridylacetate (25.0 g, 0.151 mol) and3-fluorobenzaldehyde (20.7 g, 0.167 mol) in a mixture of aceticanhydride (100 mL) and triethylamine (20 mL) was heated under reflux for5.5 hours. After standing to cool, the reaction mixture wasconcentrated. The residue was diluted with ethyl acetate and a saturatedaqueous sodium hydrogencarbonate solution, and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith a saturated aqueous sodium hydrogencarbonate solution twice andbrine, dried over anhydrous sodium sulfate and then concentrated. Theresidue was subjected to silica gel column chromatography (eluent;hexane, hexane:ethyl acetate=9:1), to give the title compound (25.5 g,62%) as a red-orange oil.

¹H NMR (400 MHz, CDCl₃) δ ppm; 1.28 (3H, t, J=7.2 Hz), 4.27 (2H, q,J=7.2 Hz), 6.70–6.75 (1H, m), 6.80–6.84 (1H, m), 6.91–6.97 (1H, m),7.12–7.18 (1H, m), 7.16 (2H, dd, J=1.6, 4.4 Hz), 7.85 (1H, s), 8.62 (2H,dd, J=1.6, 4.4 Hz).

Referential Example 2 Ethyl (E)-3-(2-furyl)-2-(4-pyridyl)-2-propenoate

The title compound was synthesized in a manner similar to that describedfor the method of Referential Example 1 using 2-furaldehyde.

¹H NMR (400 MHz, CDCl₃) δ ppm; 1.20 (3H, t, J=7.2 Hz), 4.18 (2H, q,J=7.2 Hz), 6.51 (1H, d, J=3.6 Hz), 6.54 (1H, dd, J=1.6, 3.6 Hz), 7.29(2H, dd, J=1.6, 4.4 Hz), 7.66 (1H, s), 7.69 (1H, d, J=1.6 Hz), 8.62 (2H,dd, J=1.6, 4.4 Hz).

Referential Example 3(E)-3-(3-Fluorophenyl)-2-(4-pyridyl)-2-propenenitrile

Sodium (3.0 g, 130 mmol) was dissolved in ethanol (150 mL),4-pyridylacetonitrile hydrochloride (10 g, 65 mmol) was added thereto,and then the mixture was stirred at room temperature. After 10 minutes,3-fluorobenzaldehyde (8 g, 65 mmol) was added thereto, followed bystirring as it was for 30 minutes. The resulting precipitates werecollected by filtration and washed with a small portion of water, togive the title compound (8.2 g, 56%) as a colorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 7.40–7.46 (1H, m), 7.61–7.68 (1H, m),7.75 (2H, dd, J=1.6, 4.4 Hz), 7.77–7.86 (2H, m), 8.37 (1H, s), 8.73 (2H,dd, J=1.6, 4.4 Hz).

Referential Example 4(E)-3-(3-Fluorophenyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile

To a suspension of sodium hydride (8.8 g, 0.220 mol) in1,2-dimethoxyethane (300 mL) was gradually added diethylcyanomethylphosphonate (19.7 g, 0.122 mol) at room temperature under anatmosphere of nitrogen gas. After stirring for 15 minutes,5-bromo-2-methoxypyridine (20.0 g, 0.106 mol) andtetrakis(triphenylphosphine)palladium(0) (2.0 g, 1.73 mmol) weresequentially added thereto, and the mixture was heated to 90° C. andstirred for 6 hours. After standing to cool, the reaction mixture wasfurther cooled on ice. 3-Fluorobenzaldehyde (13.7 g, 0.110 mol) wasadded dropwise thereinto under an atmosphere of nitrogen gas at 1° C. to4° C. over 1.5 hours, and the mixture was stirred for further 2.5 hourswhile gradually elevating to room temperature. The reaction mixture wasdiluted with a saturated aqueous ammonium chloride solution and ethylacetate, and then the aqueous layer was extracted with ethyl acetate.The combined organic layers were washed with a saturated aqueousammonium chloride solution twice, dried over anhydrous sodium sulfateand then concentrated. The residue was suspended in methanol, and theresulting solid was collected by filtration and washed with diethylether and hexane, to give the title compound (7.80 g, 29%) as acolorless solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.92 (3H, s), 7.00 (1H, d, J=8.8 Hz),7.34–7.40 (1H, m), 7.57–7.64 (1H, m), 7.69–7.78 (2H, m), 8.03 (1H, s),8.11 (1H, dd, J=2.6, 8.8 Hz), 8.53 (1H, d, J=2.6 Hz).

Referential Example 5(E)-3-(2-Furyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile

The title compound was obtained (16.3 g, 68%) as a yellow solid in amanner similar to that described for Referential Example 4 from furfuralinstead of 3-fluorobenzaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.90 (3H, s), 6.75 (1H, dd, J=1.6, 3.6Hz), 6.94 (1H, dd, J=0.8, 8.8 Hz), 7.11 (1H, dd, J=0.8, 3.6 Hz), 7.83(1H, s), 8.00 (1H, dd, J=0.8, 1.6 Hz), 8.04 (1H, dd, J=2.8, 8.8 Hz),8.46 (1H, dd, J=0.8, 2.8 Hz).

Example 12-Amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

(Method 1)

Sodium (3.2 g, 139 mmol) was dissolved in ethanol (200 mL), and then4-pyridylacetonitrile (10.0 g, 64.7 mmol), 3-fluorobenzaldehyde (7.3 mL,68.8 mmol) and guanidine hydrochloride (7.0 g, 73.3 mmol) weresuccessively added thereto under ice-cooling, followed by heating underreflux for two days. The insoluble matters were filtered off, and thefiltrate was concentrated. The residue was subjected to silica gelcolumn chromatography (eluent; dichloromethane,dichloromethane:methanol=20:1, 10:1, 5:1), to give the 5,6-dihydro formof the title compound (13.6 g) as a crude product. To the crude productwas added sulfur (26.4 g, 82.3 mmol in terms of sulfur), followed byheating at 185° C. for 2.5 hours. After standing to cool, the reactionmixture was suspended in methanol. The insoluble matters were filteredoff and washed with 2N hydrochloric acid. After concentrating methanolfrom the filtrate, the residue was washed with ethyl acetate twice. Theaqueous layer was adjusted to pH 11 with a 5N aqueous sodium hydroxidesolution, and washed with ethyl acetate twice. The aqueous layer wasneutralized with 2N hydrochloric acid, and the resulting crystals werecollected by filtration, and washed with water and ethyl acetate, togive the title compound (6.2 g, 34%) as a colorless solid. In thisprocess, the title compound could also be obtained by isolating(E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenenitrile and thensubjecting it to cyclization reaction with guanidine in a manner similarto that described for Referential Example 3.

(Method 2)

Sodium (3.4 g, 147 mmol) was dissolved in ethanol (500 mL), and ethyl(E)-3-(3-fluorophenyl)-2-(4-pyridyl)-2-propenoate (33 g, 121 mmol) andguanidine hydrochloride (13.9 g, 146 mmol) were added thereto, followedby heating under reflux for 13 hours. After standing to cool, thesolvent was removed and to the residue was added tetrahydrofuran (500mL). The insoluble matters were filtered off, and the filtrate wasconcentrated. To a solution of the residue in tetrahydrofuran (1500 mL)and methanol (100 mL) was added activated manganese dioxide (250 g),followed by heating under reflux. After 2 hours, additional activatedmanganese dioxide (100 g) was added and the mixture was heated underreflux further for one and a quarter hour. After standing to cool,manganese dioxide was filtered off through Celite, and washed withtetrahydrofuran and methanol. The combined filtrates were concentrated,and to the residue was added acetonitrile. The resulting precipitateswere collected by filtration, to give the title compound (15 g, 44%) asa yellow powder.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.86 (2H, br s), 6.96 (1H, d, J=7.6Hz), 7.00–7.07 (3H, m), 7.00–7.15 (1H, m), 7.20–7.28 (1H, m), 8.34 (2H,d, J=3.2 Hz); MS m/e (ESI) 283 (MH⁺).

Example 2 2-Amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor the Method 1 of Example 1 from 2-furaldehyde.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 6.48 (1H, dd, J=1.6, 3.6 Hz), 6.54 (1H,dd, J=0.8, 3.6 Hz), 6.91 (2H, br s), 7.21 (2H, dd, J=1.6, 4.6 Hz), 7.54(1H, dd, J=0.8, 1.6 Hz), 8.52 (2H, dd, J=1.6, 4.6 Hz); MS m/e (ESI) 255(MH⁺).

Examples 3 and 4 Example 3 2-Amino-6-(3-fluorophenyl)-3-methyl-5-(4PCTpyridyl)-3,4-dihydro-4-pyrimidinone

Example 46-(3-Fluorophenyl)-3-methyl-2-(methylamino)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

To a solution of2-amino-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone (100mg, 0.354 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride(15 mg, 0.375 mmol in terms of 60% suspension) at 0° C. under anatmosphere of nitrogen gas, followed by stirring. After 10 minutes,iodomethane (30 μL, 0.482 mmol) was added thereto, followed by stirringfurther for 30 minutes. The reaction mixture was diluted with ethylacetate and a saturated aqueous ammonium chloride solution. The organiclayer was washed with a saturated aqueous ammonium chloride solution,water and brine, dried over anhydrous sodium sulfate and thenconcentrated. The residue was subjected to silica gel plate (developingsolvent; dichloromethane:methanol=10:1), to give2-amino-6-(3-fluorophenyl)-3-methyl-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone(19 mg, 18%) and6-(3-fluorophenyl)-3-methyl-2-(methylamino)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone(6 mg, 5%) as a colorless solid, respectively.

2-Amino-6-(3-fluorophenyl)-3-methyl-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.36 (3H, s), 6.93–7.16 (3H, m), 7.04(2H, d, J=4.8 Hz), 7.20–7.29 (1H, m), 7.50 (2H, br s), 8.35 (2H, d,J=4.8 Hz); MS m/e (ESI) 297 (MH⁺).

6-(3-Fluorophenyl)-3-methyl-2-(methylamino)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 2.93 (3H, d, J=4.4 Hz), 3.35 (3H, s),6.99–7.16 (3H, m), 7.05 (2H, d, J=5.8 Hz), 7.22–7.29 (1H, m), 7.49 (1H,q, J=4.4 Hz), 8.37 (2H, d, J=5.8 Hz); MS m/e (ESI) 311 (MH⁺).

Example 52-Amino-3-ethyl-6-(3-fluorophenyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor Example 3 from ethyl iodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.19 (3H, t, J=7.2 Hz), 3.99 (2H, q,J=7.2 Hz), 6.94–6.99 (1H, m), 7.01–7.14 (2H, m), 7.05 (2H, d, J=5.6 Hz),7.21–7.28 (1H, m), 7.53 (2H, br s), 8.35 (2H, d, J=5.6 Hz); MS m/e (ESI)311 (MH⁺).

Example 62-Amino-6-(3-fluorophenyl)-3-propyl-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor Example 3 from n-propyl iodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.90 (3H, t, J=7.6 Hz), 1.58 (2H, sex,J=7.6 Hz), 3.85 (2H, t, J=7.6 Hz), 6.93–7.16 (3H, m), 7.04 (2H, d, J=5.2Hz), 7.19–7.28 (1H, m), 7.52 (2H, br s), 8.34 (2H, d, J=5.2 Hz); MS m/e(ESI) 325 (MH⁺).

Example 72-Amino-6-(2-furyl)-3-methyl-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor Example 3 from2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.32 (3H, s), 6.42 (1H, d, J=3.6 Hz),6.46 (1H, dd, J=1.6, 3.6 Hz), 7.14 (2H, d, J=4.6 Hz), 7.39 (2H, br s),7.55 (1H, s), 8.50 (2H, d, J=4.6 Hz); MS m/e (ESI) 269 (MH⁺).

Example 82-Amino-3-ethyl-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor Example 3 from2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and ethyliodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.15 (3H, t, J=7.2 Hz), 3.95 (2H, q,J=7.2 Hz), 6.42 (1H, dd, J=0.8, 3.6 Hz), 6.46 (1H, dd, J=1.6, 3.6 Hz),7.15 (2H, dd, J=1.6, 4.4 Hz), 7.24 (2H, br s), 7.55 (1H, dd, J=0.8, 1.6Hz), 8.49 (2H, dd, J=1.6, 4.4 Hz); MS m/e (ESI) 283 (MH⁺).

Example 92-Amino-6-(2-furyl)-3-propyl-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor Example 3 from2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone andn-propyl iodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 0.90 (3H, t, J=7.6 Hz), 1.58 (2H, sex,J=7.6 Hz), 3.85 (2H, t, J=7.6 Hz), 6.43 (1H, dd, J=0.8, 3.6 Hz), 6.45(1H, dd, J=1.6, 3.6 Hz), 7.14 (2H, dd, J=1.2, 4.4 Hz), 7.40 (2H, br s),7.55 (1H, dd, J=0.8, 1.6 Hz), 8.54 (2H, dd, J=1.2, 4.4 Hz); MS m/e (ESI)297 (MH⁺).

Example 103-allyl-2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor Example 3 from2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and allylbromide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.57 (2H, d, J=5.0 Hz), 5.12–5.20 (2H,m), 5.85 (1H, ddt, J=5.0, 10.4, 17.2 Hz), 6.45 (1H, d, J=3.2 Hz), 6.47(1H, dd, J=1.6, 3.2 Hz), 7.15 (2H, dd, J=1.2, 4.8 Hz), 7.34 (2H, br s),7.56 (1H, d, J=1.6 Hz), 8.49 (2H, dd, J=1.2, 4.8 Hz); MS m/e (FAB) 295(MH⁺).

Example 112-Amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was synthesized in a manner similar to that describedfor the Method 2 of Example 1 from(E)-3-(3-fluorophenyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.77 (3H, s), 6.66 (1H, dd, J=0.8, 8.4Hz), 6.76 (2H, brs), 6.96–6.98 (1H, m), 7.02–7.09 (2H, m), 7.21–7.25(1H, m), 7.37 (1H, dd, J=2.4, 8.4 Hz), 7.72 (1H, dd, J=0.8, 2.4 Hz),11.29 (1H, brs).

Example 122-Amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3-methyl-3,4-dihydro-4-pyrimidinone

To a solution of2-amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone(1.0 g, 3.2 mmol) in N,N-dimethylformamide (3 mL) was added sodiumhydride (77 mg, 3.2 mmol). After stirring for 10 minutes, iodomethane(454 mg, 0.2 mL, 3.2 mmol) was added thereto, and the mixture wasstirred at room temperature for 2 hours. After removing the solvent fromthe reaction mixture, the residue was washed with water, to give thetitle compound (600 mg).

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.32 (3H, s), 3.78 (3H, s), 6.68 (1H,dd, J=0.8, 8.8 Hz), 6.97–7.12 (3H, m), 7.23–7.28 (1H, m), 7.36 (2H,brs), 7.39 (1H, dd, J=2.4, 8.8 Hz), 7.74 (1H, dd, J=0.8, 2.4 Hz).

Example 132-Amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

In a mixture solution of acetic acid and 48% hydrogen bromide,2-amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3-methyl-3,4-dihydro-4-pyrimidinonewas stirred at 100° C. for 2 hours. After cooling, the reaction solutionwas basified and washed with ethyl acetate. The aqueous layer wasneutralized with diluted hydrochloric acid, and the resulting solid wascollected by filtration, to give the title compound.

¹H NMR (400 MHz, DMSO-d₆-D₂O) δ ppm; 3.33 (3H, s), 6.17 (1H, d, J=9.4Hz), 6.94 (1H, d, J=2.4 Hz), 7.09 (1H, dd, J=2.4, 9.4 Hz), 7.11–7.14(3H, m), 7.28–7.35 (1H, m).

Example 142-Amino-6-(3-fluorophenyl)-3-methyl-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

To a solution of2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone(20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassiumcarbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol),followed by stirring at 50° C. for 16 hours. After filtering off theinsoluble matters, the filtrate was purified by HPLC, to give the titlecompound (4 mg).

¹H NMR (400 MHz, CD₃OD) δ ppm; 3.47 (3H, s), 3.48 (3H, s), 6.39 (1H, d,J=9.2 Hz), 7.02–7.08 (1H, m), 7.12–7.20 (3H, m), 7.26–7.31 (1H, m), 7.42(1H, d, J=2.4 Hz).

Example 152-Amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(3-fluorophenyl)-3-methyl-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 14 from iodoethane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.12 (3H, t, J=7.2 Hz), 3.48 (3H, s),3.88 (2H, q, J=7.2 Hz), 6.44 (1H, dd, J=0.8, 9.2 Hz), 7.02–7.07 (1H, m),7.10–7.16 (2H, m), 7.27–7.28 (2H, m), 7.31 (1H, dd, J=2.4, 9.2 Hz).

Example 162-Amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1-propyl-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 14 from 1-iodopropane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 0.76 (3H, t, J=7.2 Hz), 1.53 (2H, tq,J=7.2, 7.2 Hz), 3.48 (3H, s), 3.81 (2H, t, J=7.2 Hz), 6.45 (1H, dd,J=0.6, 9.2 Hz), 7.01–7.06 (1H, m), 7.10–7.15 (2H, m), 7.23 (1H, dd,J=0.6, 2.6 Hz), 7.26–7.30 (1H, m), 7.33 (1H, dd, J=2.6, 9.2 Hz).

Example 172-Amino-5-[1-(2-fluoroethyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(3-fluorophenyl)-3-methyl-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 14 from 1-fluoro-2-iodoethane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 3.48 (3H, s), 4.17 (2H, dt, J=4.8, 26Hz), 4.53 (2H, dt, J=4.8, 47 Hz), 6.45 (1H, d, J=9.2 Hz), 7.01–7.06 (1H,m), 7.10–7.15 (2H, m), 7.25–7.28 (2H, m), 7.31 (1H, dd, J=2.4, 9.2 Hz).

Example 185-(1-allyl-6-oxo-1,6-dihydro-3-pyridinyl)-2-amino-6-(3-fluorophenyl)-3-methyl-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 14 from allyl bromide.

¹H NMR (400 MHz, CD₃OD) δ ppm; 3.48 (3H, s), 4.46 (2H, ddd, J=1.6, 3.2,5.2 Hz), 4.87–4.90 (1H, m), 5.06 (dd, J=1.2, 10.4 Hz), 5.71–5.81 (1H,m), 6.47 (1H, d, J=9.2 Hz), 7.02–7.07 (1H, m), 7.09–7.14 (2H, m), 7.19(1H, d, J=2.4 Hz), 7.25–7.31 (1H, m), 7.35 (1H, dd, J=2.4, 9.2 Hz).

Example 192-Amino-5-[1-(2-butynyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(3-fluorophenyl)-3-methyl-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 14 from 1-bromo-2-butyne.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.78 (3H, t, J=2.4 Hz), 3.49 (3H, s),4.58 (2H, q, J=2.4 Hz), 6.44 (1H, d, J=9.0 Hz), 7.03–7.18 (3H, m),7.27–7.31 (1H, m), 7.34 (1H, dd, J=2.2, 9.0 Hz), 7.44 (1H, d, J=2.2 Hz).

Example 202-Amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1-phenyl-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

In a flask were placed2-amino-6-(3-fluorophenyl)-3-methyl-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone(40 mg, 0.13 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid(31 mg, 0.26 mmol), pyridine (21 μL, 0.26 mmol) andN,N-dimethylformamide (2 mL), followed by stirring at room temperaturefor 24 hour. After filtering off the insoluble matters, the filtrate waspurified by HPLC, to give the title compound (16 mg). MS m/e (ESI) 389(MH⁺).

Example 212-Amino-6-(3-fluorophenyl)-3-methyl-5-[6-oxo-1-(3-thienyl)-1,6-dihydro-3-pyridinyl]-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 20 from 3-thienylboronic acid.

¹H NMR (400 MHz, CD₃OD) δ ppm; 3.49 (3H, s), 6.50 (1H, dd, J=0.8, 9.2Hz), 7.03 (1H, dd, J=1.6, 5.4 Hz), 7.08–7.13 (1H, m), 7.16–7.23 (2H, m),7.32–7.38 (4H, m), 7.48 (1H, dd, J=3.6, 5.4 Hz).

Example 222-Amino-3-ethyl-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 12 from ethyl iodide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.17 (3H, t, J=7.0 Hz), 3.77 (3H, s),4.02 (2H, q, J=7.0 Hz), 6.66 (1H, dd, J=0.8, 8.4 Hz), 6.95–6.98 (1H, m),7.03–7.10 (2H, m), 7.21–7.26 (1H, m), 7.38–7.40 (3H, m), 7.72 (1H, dd,J=0.8, 2.4 Hz).

Example 232-Amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 13 from2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 1.17 (3H, t=7.2 Hz), 3.96 (2H, q, J=7.2Hz), 6.14 (1H, d, J=9.2 Hz), 6.94 (1H, d, J=2.0 Hz), 7.06–7.14 (4H, m),7.28–7.34 (3H, m).

Example 242-Amino-3-ethyl-6-(3-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

To a solution of2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone(20 mg, 0.06 mmol) in dimethyl sulfoxide (1 mL) were added potassiumcarbonate (20 mg, 0.12 mmol) and iodomethane (20 μL, 0.30 mmol),followed by stirring at 50° C. for 16 hours. After filtering off theinsoluble matters, the filtrate was purified by HPLC, to give the titlecompound (4 mg).

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.32 (3H, t, J=7.2 Hz), 3.47 (3H, s),4.09 (2H, q, J=7.2 Hz), 6.40 (1H, d, J=9.4 Hz), 7.03–7.08 (1H, m), 7.11(2H, m), 7.18 (1H, dd, J=2.8, 9.4 Hz), 7.27–7.32 (1H, m), 7.43 (1H, d,J=2.8 Hz).

Example 252-Amino-3-ethyl-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 24 from iodoethane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.12 (3H, t, J=7.2 Hz), 1.32 (3H, t,J=7.2 Hz), 3.88 (2H, q, J=7.2 Hz), 4.09 (2H, q, J=7.2 Hz), 6.44 (1H, dd,J=0.4, 9.2 Hz), 7.02–7.07 (1H, m), 7.09–7.15 (2H, m), 7.31 (1H, dd,J=2.4, 9.2 Hz), 7.27–7.29 (2H, m).

Example 262-Amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1-propyl-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 24 from 1-iodopropane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 0.76 (3H, t, J=7.2 Hz), 1.32 (3H, t,J=6.8 Hz), 1.53 (2H, m), 3.81 (2H, t, J=6.8 Hz), 4.09 (2H, q, J=7.2 Hz),6.45 (1H, d, J=9.2 Hz), 7.01–7.06 (1H, m), 7.10–7.15 (2H, m), 7.33 (1H,dd, H=2.4, 9.2 Hz), 7.24 (1H, d, J=2.4 Hz), 7.26–7.30 (1H, m).

Example 272-Amino-3-ethyl-5-[1-(2-fluoroethyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 24 from 1-fluoro-2-iodoethane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.32 (3H, t, J=7.2 Hz), 4.09 (2H, q,J=7.2 Hz), 4.17 (2H, dt, J=4.8, 26 Hz), 4.53 (2H, dt, J=4.8, 47 Hz),6.45 (1H, dd, J=0.8, 9.2 Hz), 7.01–7.06 (1H, m), 7.09–7.16 (2H, m),7.25–7.30 (2H, m), 7.31 (1H, dd, J=2.4, 9.2 Hz).

Example 282-Amino-3-ethyl-6-(3-fluorophenyl)-5-[1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 24 from 3-iodopropanol.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.32 (3H, t, J=7.2 Hz), 1.70–1.77 (2H,m), 3.41 (2H, t, J=6.0 Hz), 3.96 (2H, t, J=6.8 Hz), 4.09 (2H, q, J=7.2Hz), 6.44 (1H, d, J=9.2 Hz), 7.02–7.08 (1H, m), 7.10–7.17 (2H, m),7.26–7.32 (3H, m).

Example 295-(1-allyl-6-oxo-1,6-dihydro-3-pyridinyl)-2-amino-3-ethyl-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 24 from allyl bromide.

MS m/e (ESI) 367 (MH⁺).

Example 302-Amino-5-[1-(2-butynyl)-6-oxo-1,6-dihydro-3-pyridinyl]-3-ethyl-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 24 from 1-bromo-2-butyne.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.32 (3H, t, J=7.2 Hz), 1.78 (3H, t,J=2.4 Hz), 4.09 (2H, q, J=7.2 Hz), 4.58 (2H, q, J=2.4 Hz), 6.44 (1H, dd,J=0.4, 9.2 Hz), 7.03–7.18 (3H, m), 7.27–7.32 (1H, m), 7.34 (1H, dd,J=2.4, 9.2 Hz), 7.44 (1H, dd, J=0.4, 2.4 Hz).

Example 312-Amino-5-(1-benzyl-6-oxo-1,6-dihydro-3-pyridinyl)-3-ethyl-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 24 from benzyl chloride.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.31 (3H, t, J=7.2 Hz), 4.08 (2H, q,J=7.2 Hz), 5.02 (2H, s), 6.51 (1H, d, J=9.2 Hz), 6.97–7.09 (5H, m),7.17–7.26 (4H, m), 7.29 (1H, d, J=2.4 Hz), 7.41 (1H, dd, J=2.4, 9.2 Hz).

Example 322-Amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1-phenyl-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

In a flask were placed2-amino-3-ethyl-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone(20 mg, 0.06 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid(15 mg, 0.12 mmol), pyridine (11 μL, 0.12 mmol) andN,N-dimethylformamide (1 mL), followed by stirring at room temperaturefor 24 hours. After filtering off the insoluble matters, the filtratewas purified by HPLC, to give the title compound (8 mg).

MS m/e (ESI) 403 (MH⁺).

Example 332-Amino-3-ethyl-6-(3-fluorophenyl)-5-[6-oxo-1-(3-thienyl)-1,6-dihydro-3-pyridinyl]-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 32 from 3-thienylboronic acid.

MS m/e (ESI) 409 (MH⁺).

Example 343-allyl-2-amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 12 from allyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 3.77 (3H, s), 4.59 (2H, d, J=5.2 Hz),5.17–5.22 (2H, m), 5.81–5.91 (1H, m), 6.67 (1H, dd, J=0.8, 8.4 Hz),6.97–7.00 (1H, m), 7.04–7.10 (2H, m), 7.21–7.27 (1H, m), 7.31 (2H, brs),7.40 (1H, dd, J=2.4, 8.4 Hz), 7.73 (1H, dd, J=0.8, 2.4 Hz).

Example 353-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 13 from3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm; 4.58 (2H, d, J=5.2 Hz), 5.16–5.21 (2H,m), 5.80–5.90 (1H, m), 6.15 (1H, d, J=9.2 Hz), 6.95 (1H, d, J=2.4 Hz),7.12 (1H, dd, J=2.4, 9.2 Hz), 7.09–7.16 (3H, m), 7.28–7.34 (3H, m).

Example 363-allyl-2-amino-6-(3-fluorophenyl)-5-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

To a solution of3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinonein dimethyl sulfoxide were added potassium carbonate (2 equivalents) andiodomethane (4 equivalents), followed by stirring at 50° C. for 16hours. After filtering off the insoluble matters, the filtrate waspurified by HPLC, to give the title compound.

¹H NMR (400 MHz, CD₃OD) δ ppm; 3.47 (3H, s), 4.70 (2H, ddd, J=1.6, 3.2,4.8 Hz), 5.20–5.27 (2H, m), 5.94 (1H, ddt, J=4.8, 10.4, 17.2 Hz), 6.39(1H, d, J=8.8 Hz), 7.03–7.08 (1H, m), 7.14–7.21 (3H, m), 7.26–7.32 (1H,m), 7.45 (1H, d, J=2.4 Hz).

Example 373-allyl-2-amino-5-(1-ethyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 36 from iodoethane.

¹H NMR (400 MHz, CD₃OD) δ ppm: 1.12 (3H, t, J=7.2 Hz), 3.88 (2H, q,J=7.2 Hz), 4.70 (2H, ddd, J=1.6, 3.6, 5.2 Hz), 5.23 (1H, dd, J=0.8, 10.4Hz), 5.26 (1H, dd, J=0.8, 17.2 Hz), 5.94 (1H, ddt, J=5.2, 10.4, 17.2Hz), 6.43 (1H, dd, J=0.8, 8.8 Hz), 7.03–7.08 (1H, m), 7.11–7.18 (2H, m),7.27–7.31 (2H, m), 7.33 (1H, d, J=2.8 Hz).

Example 383-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1-propyl-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 36 from 1-iodopropane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 0.76 (3H, t, J=7.2 Hz), 1.53 (2H, sex,J=7.2 Hz), 3.82 (2H, t, J=7.2 Hz), 4.70 (2H, ddd, J=2.0, 3.6, 5.0 Hz),5.20–5.27 (2H, m), 5.94 (1H, ddt, J=5.0, 10.4, 17.2 Hz), 6.44 (1H, dd,J=0.4, 9.4 Hz), 7.02–7.07 (1H, m), 7.12–7.17 (2H, m), 7.26 (1H, dd,J=0.4, 2.6 Hz), 7.26–7.31 (1H, m), 7.33 (1H, dd, J=2.6, 9.4 Hz).

Example 393-allyl-2-amino-5-[1-(2-fluoroethyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 36 from 1-fluoro-2-iodoethane.

¹H NMR (400 MHz, CD₃OD) δ ppm; 4.17 (2H, dt, J=5.2, 25.6 Hz), 4.53 (2H,dt, J=5.2, 46.8 Hz), 4.70 (2H, ddd, J=1.6, 3.6, 4.8 Hz), 5.21–5.27 (2H,m), 5.90–6.00 (1H, m), 6.45 (1H, dd, J=1.6, 8.0 Hz), 7.01–7.06 (1H, m),7.11–7.18 (2H, m), 7.25–7.33 (3H, m).

Example 403-allyl-2-amino-6-(3-fluorophenyl)-5-[1-(3-hydroxypropyl)-6-oxo-1,6-dihydro-3-pyridinyl]-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 36 from 1-bromo-3-propanol.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.74 (2H, quint, J=6.8 Hz), 3.41 (2H, t,J=6.8 Hz), 3.96 (2H, t, J=6.8 Hz), 4.70 (2H, ddd, J=1.6, 3.6, 5.0 Hz),5.23 (1H, dd, J=1.2, 15.6 Hz), 5.27 (1H, dd, J=1.2, 10.4 Hz), 5.94 (1H,ddt, J=5.0, 10.4, 15.6 Hz), 6.44 (1H, dd, J=0.8, 8.8 Hz), 7.03–7.08 (1H,m), 7.12–7.19 (2H, m), 7.28–7.32 (3H, m).

Example 413-allyl-5-(1-allyl-6-oxo-1,6-dihydro-3-pyridinyl)-2-amino-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 36 from allyl bromide.

¹H NMR (400 MHz, CD₃OD) δ ppm; 4.46 (2H, ddd, J=1.2, 2.8, 5.2 Hz), 4.69(2H, ddd, J=1.6, 3.2, 5.2 Hz), 4.86–4.90 (1H, m), 5.07 (1H, dd, J=1.6,10.4 Hz), 5.22 (1H, dd, J=0.8, 15.6 Hz), 5.26 (1H, dd, J=0.8, 10.4 Hz),5.76 (1H, ddt, J=5.2, 10.4, 15.6 Hz), 5.94 (1H, ddt, J=5.2, 10.4, 15.6Hz), 6.46 (1H, d, J=9.2 Hz), 7.02–7.07 (1H, m), 7.11–7.16 (2H, m), 7.21(1H, d, J=2.4 Hz), 7.26–7.32 (1H, m), 7.35 (1H, dd, J=2.4, 9.2 Hz).

Example 423-allyl-2-amino-5-[1-(2-butynyl)-6-oxo-1,6-dihydro-3-pyridinyl]-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 36 from 1-bromo-2-butyne.

¹H NMR (400 MHz, CD₃OD) δ ppm; 1.78 (3H, t, J=2.4 Hz), 4.58 (2H, q,J=2.4 Hz), 4.70 (2H, ddd, J=2.0, 3.6, 5.2 Hz), 5.21–5.28 (2H, m), 5.95(1H, ddt, J=5.2, 10.4, 15.6 Hz), 6.44 (1H, dd, J=0.4, 9.2 Hz), 7.04–7.09(1H, m), 7.16–7.20 (2H, m), 7.27–7.33 (1H, m), 7.35 (1H, dd, J=2.4, 9.2Hz), 7.46 (1H, dd, J=0.4, 2.4 Hz).

Example 433-allyl-2-amino-5-(1-benzyl-6-oxo-1,6-dihydro-3-pyridinyl)-6-(3-fluorophenyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 36 from benzyl chloride.

¹H NMR (400 MHz, CD₃OD) δ ppm; 4.69 (2H, ddd, J=2.0, 3.2, 4.8 Hz), 5.02(2H, s), 5.22 (1H, J=1.2, 15.6 Hz), 5.25 (1H, dd, J=1.2, 10.4 Hz), 5.93(1H, ddt, J=4.8, 10.4, 15.6 Hz), 6.50 (1H, d, J=9.2 Hz), 6.97–7.11 (5H,m), 7.11–7.26 (4H, m), 7.31 (1H, d, J=2.4 Hz), 7.41 (1H, dd, J=2.4, 9.2Hz).

Example 443-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1-phenyl-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone

In a flask were placed3-allyl-2-amino-6-(3-fluorophenyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)-3,4-dihydro-4-pyrimidinone(20 mg, 0.06 mmol), copper acetate (3 mg, 0.01 mmol), phenylboronic acid(15 mg, 0.12 mmol), pyridine (11 μL, 0.12 mmol) andN,N-dimethylformamide (1 mL), followed by stirring at room temperaturefor 24 hours. After filtering off the insoluble matters by filtration,the filtrate was purified by HPLC, to give the title compound (8 mg).

MS m/e (ESI) 415 (MH⁺).

Example 453-allyl-2-amino-6-(3-fluorophenyl)-5-[6-oxo-1-(3-thienyl)-1,6-dihydro-3-pyridinyl]-3,4-dihydro-4-pyrimidinone

The title compound was obtained in a manner similar to that describedfor Example 44 from 3-thienylboronic acid.

MS m/e (ESI) 421 (MH⁺).

Example 462-Amino-6-(2-furyl)-5-(6-methoxy-3-pyridyl)-3,4-dihydro-4-pyrimidinone

The title compound was obtained by reacting in a manner similar to thatdescribed for the Method 2 of Example 1 “from(E)-3-(2-furyl)-2-(6-methoxy-3-pyridyl)-2-propenenitrile”, and thenpurifying by HPLC.

¹H NMR (400 MHz, CD₃OD) δ ppm; 3.98 (3H, s), 6.23 (1H, dd, J=0.8, 3.6Hz), 6.53 (1H, dd, J=1.6, 3.6 Hz), 6.96 (1H, dd, J=0.8, 8.8 Hz), 7.63(1H, dd, J=2.4, 8.8 Hz), 7.74 (1H, dd, J=0.8, 1.6 Hz), 8.03 (1H, dd,J=0.8, 2.4 Hz).

The compounds represented by the above formula (I) according to thepresent invention are useful as an adenosine receptor (A₁, A_(2A),A_(2B) or A₃ receptor) antagonist and are specifically useful as anA_(2B) receptor antagonist. Test examples demonstrating the efficacy ofthe compounds of the present invention as a medicament will be describedbelow.

Test Example 1 Measurement of the Binding Ability to Adenosine A₁Receptor

A human adenosine A₁ receptor cDNA was expressed in excess in CHOK1cells, and this membrane sample was suspended at a protein concentrationof 66.7 μg/ml in 20 mM HEPES buffer, pH 7.4 (10 mM MgCl₂, 100 mM NaCl).To 0.45 ml of this membrane sample suspension were added 0.025 ml of 60nM tritium-labeled chlorocyclopentyl adenosine (³H—CCPA, from NEN Ltd.)and 0.025 ml of test compound. This mixture was left at 30° C. for 120minutes, filtered rapidly under suction through a glass fiber filter(GF/B, from Whatman), and immediately washed twice with 5 ml of 50 mMwater-cooled Tris-HCl buffer. Thereafter, the glass fiber filter wastransferred to a vial, scintillator was added thereto, and theradioactivity on the filter was measured by a liquid scintillationcounter. The inhibition of binding of ³H-CCPA to A₁ receptor by the testcompound was determined using the following formula, and from thisinhibition, 50% inhibition concentration (IC₅₀) was calculated (thefollowing equation).Inhibition (%)=[1−{(binding in the presence of the testcompound-non-specific binding)/(total binding-non-specificbinding)}]×100

In the above formula, the total binding means ³H-CCPA-boundradioactivity in the absence of the test compound; the nonspecificbinding means ³H-CCPA-bound radioactivity in the presence of 100 μM RPIA([R]-[1-methyl-2-phenylethyl] adenosine); and the binding in thepresence of the test compound means ³H-CCPA-bound radioactivity in thepresence of the test compound at predetermined concentrations. Theinhibition constant (Ki value) in the table was determined from theformula of Cheng-Prusoff.

Test Example 2 Measurement of the Binding Ability to Adenosine A_(2A)Receptor

An experiment of inhibition of binding to adenosine A_(2A) receptor wasconducted using a membrane sample (Receptor Biology Inc.) where anadenosine A_(2A) receptor cDNA was expressed in excess. This membranesample was suspended at a protein concentration of 22.2 μg/ml in 20 mMHEPES buffer, pH 7.4 (10 mM MgCl₂ and 100 mM NaCl). To 0.45 ml of thismembrane sample suspension were added 0.025 ml of 500 nM tritium-labeled2-p-[2-carboxyethyl]phenetylamino-5′-N-ethylarboxyamide adenosine(³H-CGS21680, from NEN) and 0.025 ml of test compound. This mixture wasleft at 25° C. for 90 minutes, filtered rapidly under suction through aglass fiber filter (GF/B, from Whatman), and immediately washed twicewith 5 ml of 50 mM ice-cooled Tris-HCl buffer. Thereafter, the glassfiber filter was transferred to a vial, scintillator was added thereto,and the radioactivity on the filter was measured by a liquidscintillation counter. The inhibition of binding of ³H-CGS21680 toA_(2A) receptor by the test compound was determined using the followingformula, and from this inhibition, 50% inhibition concentration (IC₅₀)was calculated.Inhibition (%)=[1−{[(binding in the presence of the testcompound)−(nonspecific binding)]/[(total binding)−(nonspecificbinding)]}]×100

Here, the total binding means ³H-CGS21680-bound radioactivity in thepresence of the test compound; the nonspecific binding means³H-CGS21680-bound radioactivity in the presence of 100 μM RPIA; and thebinding in the presence of the test compound means ³H-CGS21680-boundradioactivity in the absence of the test compound at predeterminedconcentrations. The inhibition constant (Ki value) in the table wasdetermined from the formula of Cheng-Prusoff.

Test Example 3 Experiment of Inhibition of NECA-Stimulated Production ofcAMP in Adenosine A_(2B) Receptor-Expressing Cells

CHOK1 cells where human adenosine A_(2B) receptor had been expressed inexcess were plated onto a 24-well plate at a density of 1.5×10⁵cells/well, cultured overnight, and used in the experiment. The degreeof inhibitory effect of the test compound on the amount of cAMP producedby stimulation with 30 nM 5′-N-ethylcarboxyamide adenosine (NECA fromSigma) was evaluated in terms of affinity for A_(2B) receptor. That is,the adhering cells were washed twice with 2 ml/well Krebs-Ringer buffersolution (containing 0.1% BSA; pH 7.4) and pre-incubated for 30 minutesin a volume of 0.5 ml/well. Then, a mixed solution containing NECA andthe test compound was added in a volume of 0.1 ml/well in the presenceof a phosphodiesterase inhibitor Ro-20-1724 (a product of RBI). Afterpre-incubation for 15 minutes, the reaction was terminated with 0.1 NHCl in a volume of 300 μl/well. Measurement of intracellular cAMP wascarried out using a cAMP enzyme immunoassay kit produced by Amersham.The inhibition of NECA-stimulated production of cAMP by the testcompound was determined using the following equation:Inhibition (%)=[1−{(amount of cAMP in the coexistence of NECA and thetest compound-amount of cAMP in only the Krebs-Ringer buffersolution)/(amount of cAMP upon stimulation with NECA only-amount of cAMPin only the Krebs-Ringer buffer solution)}]×100

The ability of the compound according to the present invention to bindto or the ability to antagonize adenosine receptor are as follows.

TABLE 1 K₁(nM) K₁(nM) I C₅₀(nM) Test Compound A₁ A_(2A) A_(2B) Example 21108 345 256 Example 7 966 493 71

The compounds according to the present invention or salts thereof havean excellent inhibitory action against the adenosine receptors.

Test Example 4 Evaluation of Defecation-Promoting Action

The defecation-promoting action of the adenosine A_(2B)receptor-inhibiting compound which was identified by measuring thebinding ability and inhibitory ability thereof to the adenosine receptorin Test Examples 1 to 3, a salt thereof, a solvate of them, or apharmaceutical composition containing it can be evaluated on the basisof the following method. That is, SD IGS rats (6 weeks-old, from CharlesRiver) were placed in cages (3 animals/cage) and preliminarily allowedfood and water ad libitum and raised for 1 week. Then, a taredwater-absorbing sheet was placed below each cage, and the animals werefasted but allowed water ad libitum throughout the experiment. After 1.5hours, the fecal pellets were collected from each cage and observed forabnormality before the experiment. The compound suspended or dissolvedin 0.5% (w/v) methyl cellulose (MC) was orally administered in a volumeof 5 ml/kg. On one hand, 0.5% (w/v) MC only was orally given to thecontrol group. After administration of the compound, the rats werereturned to the cage provided with a new water-absorbing sheet, and 90minutes after the administration, the fecal pellets on thewater-absorbing sheet were collected from each cage, and the externalappearance was observed, and then counted and weighed. The number offecal pellets is expressed per each cage.

The compounds according to the present invention, a salt thereof orsolvates of them have an excellent defecation-promoting action.

1. A compound represented by the following formula (I), a salt thereofor a solvate thereof:

wherein in the formula, R¹ and R² are the same as or different from eachother and each represents a hydrogen atom, an alkyl group having one tosix carbon atoms which may be substituted, an alkenyl group having twoto six carbon atoms which may be substituted, an alkynyl group havingtwo to six carbon atoms which may be substituted, a cycloalkyl grouphaving three to eight carbon atoms which may be substituted, acycloalkenyl group having three to eight carbon atoms which may besubstituted, a 5 to 14-membered non-aromatic heterocyclic group whichmay be substituted, an aromatic cyclic hydrocarbon group having six tofourteen carbon atoms which may be substituted, a 5 to 14-memberedaromatic heterocyclic group which may be substituted, an acyl grouphaving one to six carbon atoms which may be substituted or analkylsulfonyl group having one to six carbon atoms which may besubstituted; R³ represents a hydrogen atom, an alkyl group having one tosix carbon atoms which may be substituted, an alkenyl group having twoto six carbon atoms which may be substituted or an alkynyl group havingtwo to six carbon atoms which may be substituted; R⁴ represents apyridyl which may be substituted or a pyridone group which may besubstituted; and R⁵ represents an aromatic cyclic hydrocarbon grouphaving six to fourteen carbon atoms which may be substituted or a 5 to14-membered aromatic heterocyclic group which may be substituted.
 2. Thecompound according to claim 1, a salt thereof or a solvate thereof,wherein R⁴ is 4-pyridyl group which may be substituted.
 3. The compoundaccording to claim 1 or 2, a salt thereof or a solvate thereof, whereinR⁴ is represented by the formula:

wherein R⁶ represents a group selected from the following SubstituentGroup a; and the ring A may be substituted with one to four groupsselected from the following Substituent Group a: <Substituent Group a>the group consisting of a hydrogen atom, a halogen atom, a hydroxylgroup, a nitro group, a cyano group, an alkyl group having one to sixcarbon atoms which may be substituted, an alkenyl group having two tosix carbon atoms which may be substituted, an alkynyl group having twoto six carbon atoms which may be substituted, an alkoxy group having oneto six carbon atoms which may be substituted, an alkenyloxy group havingtwo to six carbon atoms which may be substituted, an alkynyloxy grouphaving two to six carbon atoms which may be substituted, an alkylthiogroup having one to six carbon atoms which may be substituted, analkenylthio group having two to six carbon atoms which may besubstituted, an alkynylthio group having two to six carbon atoms whichmay be substituted, an aliphatic acyl group having two to seven carbonatoms, a carbamoyl group which may be substituted, an arylacyl group, aheteroarylacyl group, an amino group which may be substituted, analkylsulfonyl group having one to six carbon atoms which may besubstituted, an alkenylsulfonyl group having two to six carbon atomswhich may be substituted, an alkynylsulfonyl group having two to sixcarbon atoms which may be substituted, an alkylsulfinyl group having oneto six carbon atoms which may be substituted, an alkenylsulfinyl grouphaving two to six carbon atoms which may be substituted, analkynylsulfinyl group having two to six carbon atoms which may besubstituted, a formyl group, a cycloalkyl group having three to eightcarbon atoms which may be substituted, a cycloalkenyl group having threeto eight carbon atoms which may be substituted, a 5 to 14-memberednon-aromatic heterocyclic group which may be substituted, an aromaticcyclic hydrocarbon group having six to fourteen carbon atoms which maybe substituted and a 5 to 14-membered aromatic heterocyclic group whichmay be substituted.
 4. The compound according to claim 3, a salt thereofor a solvate thereof, wherein R⁴ is represented by the formula:

or the formula:

wherein in the formulae (III) and (IV), R⁶ represents a group selectedfrom Substituent Group a as defined in claim 3; and the ring Arepresents a nitrogen-containing 6-membered ring which may besubstituted with one to four groups selected from the above mentionedSubstituent Group a.
 5. The compound according to claim 1 or 2, a saltthereof or a solvate thereof, wherein R⁴ is 4-pyridyl group which may besubstituted with one or two substituent(s).
 6. The compound according toclaim 1, a salt thereof or a solvate thereof, wherein R¹ and/or R² is ahydrogen atom, an alkyl group which may be substituted, or an acyl grouphaving one to six carbon atoms which may be substituted.
 7. The compoundaccording to claim 1, a salt thereof or a solvate thereof, wherein R⁵ isphenyl group, pyrrolyl group, pyridyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, thienyl group, thiazolyl group,furyl group, naphthyl group, quinolinyl group, isoquinolinyl group,phthalazinyl group, naphthyridinyl group, indolyl group or isoindolylgroup, each of which may be substituted.
 8. A pharmaceutical compositioncomprising the compound according to claim 1, a salt thereof or asolvate thereof; and a pharmaceutically acceptable carrier.
 9. Thecomposition according to claim 8, which is an adenosine receptorantagonist.
 10. The composition according to claim 8, which is anadenosine A₂ receptor antagonist.
 11. The composition according to claim8, which is adenosine A_(2B) receptor antagonist.
 12. A method forpromoting defecation, which comprises administering a pharmacologicallyeffective amount of the compound of claim 1, a salt thereof or a solvatethereof to a patient in need thereof.
 13. A method for treating orimproving irritable bowel syndrome, constipation accompanying irritablebowel syndrome, organic constipation, constipation accompanyingenteroparalytic ileus, constipation accompanying congenital digestivetract dysfunction or constipation accompanying ileus, said methodcomprising: administering a pharmaceutically effective amount of thecompound of claim 1, a salt thereof or a solvate of them to a patient inneed thereof.
 14. The method according to claim 13, said administrationstep is to evacuate intestinal tracts at the time of examination ofdigestive tracts or before and after an operation.
 15. The methodaccording to claim 13, wherein said constipation is functionalconstipation.
 16. A method for promoting defecation, which comprisesadministering the pharmaceutical composition of claim 8 to a patient inneed thereof.
 17. A method for treating or improving irritable bowelsyndrome, constipation accompanying irritable bowel syndrome, organicconstipation, constipation accompanying enteroparalytic ileus,constipation accompanying congenital digestive tract dysfunction orconstipation accompanying ileus, said method comprising: administeringthe pharmaceutical composition of claim 8 to a patient in need thereof.18. The method according to claim 17, said administration step is toevacuate intestinal tracts at the time of examination of digestivetracts or before and after an operation.
 19. The method according toclaim 17, wherein said constipation is functional constipation.